Organic compounds

ABSTRACT

The present invention provides compounds of the formula 
                         
which are activators of glucokinase activity and, thus, may be employed as therapeutic agents for the treatment of glucokinase mediated conditions. Accordingly, the compounds of formula (I) may be employed for the prevention and the treatment of impaired glucose tolerance, type 2 diabetes and obesity.

This application is the National Stage of Application No.PCT/US2006/038200, filed on Sep. 28, 2006, which claims benefit under 35U.S.C. §119(e) of U.S. Provisional Application No. 60/722,628, filedSep. 30, 2005, the contents of which are incorporated herein byreference in their entirety.

The present invention relates to certain sulfonamide derivatives,pharmaceutical compositions containing them, and to methods of treatingglucokinase mediated conditions, in particular, impaired glucosetolerance and type 2 diabetes, by employing such compounds.

Accordingly, the present invention provides compounds of the formula

wherein

-   -   Q combined together with the carbon and nitrogen atoms to which        it is attached form a 5- to 6-membered monocyclic heteroaromatic        ring; or    -   Q combined together with the carbon and nitrogen atoms to which        it is attached form a 9- to 10-membered bicyclic heterocycle;    -   R₁ and R₂ are, independently from each other, hydrogen, halogen,        cyano, nitro, optionally substituted alkyl, alkoxy, alkylthio,        alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl,        sulfamoyl, optionally substituted amino, aryl or heterocyclyl;        or    -   R₂ is absent;    -   R₃ is C₃-C₆ cycloalkyl or C₃-C₆ heterocyclyl;    -   R₄ is hydrogen, halogen, cyano, lower alkyl or lower alkoxy;    -   R₅ is hydrogen, optionally substituted alkyl, or cycloalkyl;    -   R₆ is —(CR₇R₈)_(m)—W—R₉ in which        -   R₇ and R₈ are, independently from each other, hydrogen,            optionally substituted alkyl or cycloalkyl; or        -   R₇ and R₈ combined are alkylene which together with the            carbon atom to which they are attached form a 3- to            7-membered ring;        -   m is zero or an integer from 1 to 5;        -   W is —NR₁₀— in which            -   R₁₀ is hydrogen, optionally substituted alkyl or                heterocyclyl; or            -   R₁₀ is —C(O)R₁₁, —C(O)OR₁₁, or —C(O)NR₁₂R₁₃ in which                -   R₁₁ and R₁₂ are, independently from each other,                    optionally substituted alkyl, cycloalkyl, aryl,                    heteroaryl, aralkyl or heteroaralkyl;                -   R₁₃ is hydrogen or lower alkyl; or                -   R₁₃ and R₁₂ combined are alkylene which together                    with the nitrogen atom to which they are attached                    form a 4- to 7-membered ring; or        -   W is absent;        -   R₉ is hydrogen, optionally substituted C₁-C₇ alkyl,            cycloalkyl, aryl or heterocyclyl; or        -   R₉ and R₁₀ combined are alkylene which together with the            nitrogen atom to which they are attached form a 4- to            7-membered ring; or    -   R₆ and R₅ combined are alkylene which together with the nitrogen        atom to which they are attached form a 4- to 7-membered ring        which may be optionally substituted, or may contain 1 to 3 other        heteroatoms selected from oxygen, nitrogen and sulfur, or may be        part of another ring;        or an enantiomer thereof; or an enantiomeric mixture thereof; or        a pharmaceutically acceptable salt thereof.

The compounds of the present invention provide pharmacological agentswhich are glucokinase activators and, thus, may be employed for thetreatment of glucokinase mediated conditions. Accordingly, the compoundsof formula (I) may be employed for prevention and treatment of impairedglucose tolerance, type 2 diabetes and obesity.

Listed below are definitions of various terms used to describe thecompounds of the present invention. These definitions apply to the termsas they are used throughout the specification unless they are otherwiselimited in specific instances either individually or as part of a largergroup, e.g., wherein an attachment point of a certain group is limitedto a specific atom within that group, the point of attachment is definedby an arrow at the specific atom.

The term “optionally substituted alkyl” refers to unsubstituted orsubstituted alkyl groups, i.e., straight- or branched-chain hydrocarbongroups having 1-20 carbon atoms, preferably 1-10 carbon atoms. Exemplaryunsubstituted alkyl groups include methyl, ethyl, propyl, isopropyl,n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl,4,4-dimethylpentyl, octyl and the like. Substituted alkyl groupsinclude, but are not limited to, alkyl groups substituted by one or moreof the following groups: halogen, hydroxy, alkanoyl, alkoxy,alkanoyloxy, thiol, alkylthio, alkylthiono, sulfonyl, sulfamoyl,carbamoyl, cyano, carboxy, acyl, aryl, alkenyl, alkynyl, aralkoxy,guanidino, optionally substituted amino, heterocyclyl includingimidazolyl, furyl, thienyl, thiazolyl, pyrrolidyl, pyridyl, pyrimidyland the like.

The term “lower alkyl” refers to those alkyl groups as described abovehaving 1-7, preferably 2-4 carbon atoms.

The term “halogen” or “halo” refers to fluorine, chlorine, bromine andiodine.

The term “alkenyl” refers to any of the above alkyl groups having atleast two carbon atoms and further containing a carbon to carbon doublebond at the point of attachment. Groups having 2-4 carbon atoms arepreferred.

The term “alkynyl” refers to any of the above alkyl groups having atleast two carbon atoms and further containing a carbon to carbon triplebond at the point of attachment. Groups having 2-4 carbon atoms arepreferred.

The term “alkylene” refers to a straight-chain bridge of 2-6 carbonatoms connected by single bonds, e.g., —(CH₂)_(X)—, wherein x is 2-6,which may be interrupted with one or more heteroatoms selected from O,O—C(O)—, S, S(O), S(O)₂ or NR, wherein R may be hydrogen, alkyl,cycloalkyl, aryl, heterocyclyl, aralkyl, heteroaralkyl, acyl, carbamoyl,sulfonyl, alkoxycarbonyl, aryloxycarbonyl or aralkoxycarbonyl and thelike. The alkylene may further be substituted with one or moresubstituents selected from optionally substituted alkyl, cycloalkyl,aryl, heterocyclyl, oxo, halogen, hydroxy, carboxy, alkoxy,alkoxycarbonyl and the like; and it may be part of another ring.

The term “cycloalkyl” refers to optionally substituted monocyclic,bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms, each ofwhich may contain one or more carbon to carbon double bonds, or thecycloalkyl may be substituted by one or more substituents, such asalkyl, halo, oxo, hydroxy, alkoxy, alkanoyl, acylamino, carbamoyl,alkylamino, dialkylamino, thiol, alkylthio, cyano, carboxy,alkoxycarbonyl, sulfonyl, sulfonamido, sulfamoyl, heterocyclyl and thelike.

Exemplary monocyclic hydrocarbon groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl andcyclohexenyl and the like.

Exemplary bicyclic hydrocarbon groups include bornyl, indyl,hexahydroindyl, tetrahydronaphthyl, decahydronaphthyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like.

Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

The term “alkoxy” refers to alkyl-O—.

The term “alkanoyl” refers to alkyl-C(O)—.

The term “alkanoyloxy” refers to alkyl-C(O)—O—.

The terms “alkylamino” and “dialkylamino” refer to alkyl-NH— and(alkyl)₂N—, respectively.

The term “alkanoylamino” refers to alkyl-C(O)—NH—.

The term “alkylthio” refers to alkyl-S—.

The term “trialkylsilyl” refers to (alkyl)₃Si—.

The term “trialkylsilyloxy” refers to (alkyl)₃SiO—.

The term “alkylthiono” refers to alkyl-S(O)—.

The term “alkylsulfonyl” refers to alkyl-S(O)₂—.

The term “alkoxycarbonyl” refers to alkyl-O—C(O)—.

The term “alkoxycarbonyloxy” refers to alkyl-O—C(O)O—.

The term “carbamoyl” refers to H₂NC(O)—, alkyl-NHC(O)—, (alkyl)₂NC(O)—,aryl-NHC(O)—, alkyl(aryl)-NC(O)—, heteroaryl-NHC(O)—,alkyl(heteroaryl)-NC(O)—, aralkyl-NHC(O)—, alkyl(aralkyl)-NC(O)— and thelike.

The term “sulfamoyl” refers to H₂NS(O)₂—, alkyl-NHS(O)₂—,(alkyl)₂NS(O)₂—, aryl-NHS(O)₂—, alkyl(aryl)-NS(O)₂—, (aryl)₂NS(O)₂—,heteroaryl-NHS(O)₂—, aralkyl-NHS(O)₂—, heteroaralkyl-NHS(O)₂— and thelike.

The term “sulfonamido” refers to alkyl-S(O)₂—NH—, aryl-S(O)₂—NH—,aralkyl-S(O)₂—NH—, heteroaryl-S(O)₂—NH—, heteroaralkyl-S(O)₂—NH—,alkyl-S(O)₂—N(alkyl)-, aryl-S(O)₂—N(alkyl)-, aralkyl-S(O)₂—N(alkyl)-,heteroaryl-S(O)₂—N(alkyl)-, heteroaralkyl-S(O)₂—N(alkyl)- and the like.

The term “sulfonyl” refers to alkylsulfonyl, arylsulfonyl,heteroarylsulfonyl, aralkylsulfonyl, heteroaralkylsulfonyl and the like.

The term “optionally substituted amino” refers to an amino group whichmay optionally be substituted by substituents such as optionallysubstituted alkyl, acyl, sulfonyl, alkoxycarbonyl, cycloalkoxycarbonyl,aryloxycarbonyl, heteroaryloxycarbonyl, aralkoxycarbonyl,heteroaralkoxycarbonyl, carbamoyl and the like.

The term “aryl” refers to monocyclic or bicyclic aromatic hydrocarbongroups having 6-12 carbon atoms in the ring portion, such as phenyl,biphenyl, naphthyl and tetrahydronaphthyl, each of which may optionallybe substituted by 1-4 substituents, such as optionally substitutedalkyl, trifluoromethyl, cycloalkyl, halo, hydroxy, alkoxy, acyl,alkanoyloxy, aryloxy, optionally substituted amino, thiol, alkylthio,arylthio, nitro, cyano, carboxy, alkoxycarbonyl, carbamoyl, alkylthiono,sulfonyl, sulfonamido, heterocyclyl and the like.

The term “monocyclic aryl” refers to optionally substituted phenyl asdescribed under aryl.

The term “aralkyl” refers to an aryl group bonded directly through analkyl group, such as benzyl.

The term “aralkanoyl” refers to aralkyl-C(O)—.

The term “aralkylthio” refers to aralkyl-S—.

The term “aralkoxy” refers to an aryl group bonded directly through analkoxy group.

The term “arylsulfonyl” refers to aryl-S(O)₂—.

The term “arylthio” refers to aryl-S—.

The term “aroyl” refers to aryl-C(O)—.

The term “aroyloxy” refers to aryl-C(O)—O—.

The term “aroylamino” refers to aryl-C(O)—NH—.

The term “aryloxycarbonyl” refers to aryl-O—C(O)—.

The term “heterocyclyl” or “heterocyclo” refers to an optionallysubstituted, fully saturated or unsaturated, aromatic or nonaromaticcyclic group, e.g., which is a 4- to 7-membered monocyclic, 7- to12-membered bicyclic or 10- to 15-membered tricyclic ring system, whichhas at least one heteroatom in at least one carbon atom-containing ring.Each ring of the heterocyclic group containing a heteroatom may have 1,2 or 3 heteroatoms selected from nitrogen atoms, oxygen atoms and sulfuratoms, where the nitrogen and sulfur heteroatoms may also optionally beoxidized. The heterocyclic group may be attached at a heteroatom or acarbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl, pyrrolyl,pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl,imidazolidinyl, triazolyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridinyl,pyrazinyl, pyrimidinyl, pyridazinyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,1,3-dioxolane and tetrahydro-1,1-dioxothienyl,1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl and the like.

Exemplary bicyclic heterocyclic groups include indolyl, dihydroidolyl,benzothiazolyl, 4,5,6,7-tetrahydro-benzothiazolyl, benzoxazinyl,benzoxazolyl, benzothienyl, benzothiazinyl, thiazolo[5,4-b]pyridinyl,thiazolo[5,4-d]pyrimidinyl, oxazolo[5,4-b]pyridinyl,6,7-dihydro-4H-thiopyrano[4,3-d]thiazolyl,6,7-dihydro-4H-pyrano[4,3-d]thiazolyl,4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridinyl,4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridinyl,5,6,7,8-tetrahydro-triazolo[1,5-a]pyridinyl, quinuclidinyl, quinolinyl,tetrahydroquinolinyl, decahydroquinolinyl, isoquinolinyl,tetrahydroisoquinolinyl, decahydroisoquinolinyl, benzimidazolyl,benzopyranyl, indolizinyl, benzofuryl, chromonyl, coumarinyl,benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]-pyridinyl] orfuro[2,3-b]pyridinyl), dihydroisoindolyl,1,3-dioxo-1,3-dihydroisoindol-2-yl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), phthalazinyl and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl,dibenzoazepinyl, dithienoazepinyl, benzindolyl, phenanthrolinyl,acridinyl, phenanthridinyl, phenoxazinyl, phenothiazinyl, xanthenyl,carbolinyl and the like.

The term “heterocyclyl” includes substituted heterocyclic groups.Substituted heterocyclic groups refer to heterocyclic groups substitutedwith 1, 2 or 3 substituents selected from the group consisting of thefollowing:

-   -   (a) optionally substituted alkyl;    -   (b) hydroxyl (or protected hydroxyl);    -   (c) halo;    -   (d) oxo, i.e., ═O;    -   (e) optionally substituted amino;    -   (f) alkoxy;    -   (g) cycloalkyl;    -   (h) free or esterified carboxy;    -   (i) heterocyclyl;    -   (j) alkylthio;    -   (k) alkylthiono;    -   (l) nitro;    -   (m) cyano;    -   (n) sulfamoyl;    -   (o) alkanoyloxy;    -   (p) aroyloxy;    -   (q) arylthio;    -   (r) aryloxy;    -   (s) sulfamoyl;    -   (t) sulfonyl;    -   (u) carbamoyl;    -   (v) aralkyl; and    -   (w) aryl optionally substituted with alkyl, cycloalkyl, alkoxy,        hydroxyl, amino, acylamino, alkylamino, dialkylamino or halo.

The term “heterocyclooxy” denotes a heterocyclic group bonded through anoxygen bridge.

The term “heteroaryl” refers to an aromatic heterocycle, e.g.,monocyclic or bicyclic aryl, such as pyrrolyl, pyrazolyl, imidazolyl,triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furyl,thienyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl,benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl, isoquinolinyl,benzimidazolyl, benzofuryl and the like, optionally substituted by,e.g., lower alkyl, lower alkoxy or halo.

The term “heteroarylsulfonyl” refers to heteroaryl-S(O)₂—.

The term “heteroaroyl” refers to heteroaryl-C(O)—.

The term “heteroaryloxycarbonyl” refers to heteroaryl-O—C(O)—.

The term “heteroaroylamino” refers to heteroaryl-C(O)NH—.

The term “heteroaralkyl” refers to a heteroaryl group bonded through analkyl group.

The term “heteroaralkanoyl” refers to heteroaralkyl-C(O)—.

The term “heteroaralkanoylamino” refers to heteroaralkyl-C(O)NH—.

The term “acyl” refers to alkanoyl, aroyl, heteroaroyl, aralkanoyl,heteroaralkanoyl and the like.

The term “acylamino” refers to alkanoylamino, aroylamino,heteroaroylamino, aralkanoylamino, heteroaralkanoylamino and the like.

The term “esterified carboxy” refers to optionally substitutedalkoxycarbonyl, cycloalkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,heterocyclooxycarbonyl and the like.

Pharmaceutically acceptable salts of the compounds of the presentinvention refer to salts formed with acids, namely acid addition salts,such as of mineral acids, organic carboxylic acids and organic sulfonicacids, e.g., hydrochloric acid, maleic acid and methanesulfonic acid,respectively.

Similarly, pharmaceutically acceptable salts of the compounds of theinvention refer to salts formed with bases, namely cationic salts, suchas alkali and alkaline earth metal salts, e.g., sodium, lithium,potassium, calcium and magnesium, as well as ammonium salts, e.g.,ammonium, trimethylammonium, diethylammonium andtris(hydroxymethyl)-methyl-ammonium salts and salts with amino acidsprovided an acidic group constitutes part of the structure.

As described herein above, the present invention provides certainsulfonamide derivatives of formula (I), pharmaceutical compositionscontaining them, methods for preparing said compounds, and methods oftreating glucokinase mediated conditions by administration of atherapeutically effective amount of a compound of the present invention,or a pharmaceutical composition thereof.

Preferred are the compounds of formula (I), designated as the A group,wherein

-   -   R₁ and R₂ are, independently from each other, hydrogen, halogen,        cyano, nitro, optionally substituted alkyl, alkoxy, alkylthio,        alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl,        sulfamoyl, optionally substituted amino, aryl or heterocyclyl;        or    -   R₂ is absent;    -   R₃ is cyclopentyl;    -   R₄ is hydrogen;    -   R₅ is hydrogen or lower alkyl;    -   R₆ is —(CR₇R₈)_(m)—W—R₉ in which        -   R₇ and R₈ are independently hydrogen or optionally            substituted lower alkyl;        -   m is zero or an integer from 1 to 5;        -   W is —NR₁₀— in which            -   R₁₀ is hydrogen or lower alkyl; or            -   R₁₀ is —C(O)R₁₁, —C(O)OR₁₁, or —C(O)NR₁₂R₁₃ in which                -   R₁₁ and R₁₂ are, independently from each other,                    optionally substituted alkyl, cycloalkyl, aryl,                    heteroaryl, aralkyl or heteroaralkyl;                -   R₁₃ is hydrogen or lower alkyl; or                -   R₁₃ and R₁₂ combined are alkylene which together                    with the nitrogen atom to which they are attached                    form a 5- to 7-membered ring; or        -   W is absent;        -   R₉ is hydrogen, optionally substituted C₁-C₇ alkyl,            cycloalkyl, aryl or heterocyclyl; or        -   R₉ and R₁₀ combined are alkylene which together with the            nitrogen atom to which they are attached form a 5- to            7-membered ring; or    -   R₆ and R₅ combined are alkylene which together with the nitrogen        atom to which they are attached form a 4- to 7-membered ring        which may be optionally substituted, or may contain 1 to 3 other        heteroatoms selected from oxygen, nitrogen and sulfur, or may be        part of another ring;        or an enantiomer thereof; or an enantiomeric mixture thereof; or        a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the A group, designated as the B group,wherein

-   -   Q combined together with the carbon and nitrogen atoms to which        it is attached form a 5- to 6-membered monocyclic heteroaromatic        ring which is selected from the group consisting of

-   -   R₅ is hydrogen or lower alkyl;    -   R₆ is —(CR₇R₈)_(m)—W—R₉ in which        -   R₇ and R₈ are hydrogen;        -   m is an integer from 2 to 5;        -   W is —NR₁₀— in which            -   R₁₀ is hydrogen or lower alkyl; or            -   R₁₀ is —C(O)R₁₁, —C(O)OR₁₁, or —C(O)NR₁₂R₁₃ in which                -   R₁₁ and R₁₂ are, independently from each other,                    optionally substituted alkyl, cycloalkyl, aryl,                    heteroaryl, aralkyl or heteroaralkyl;                -   R₁₃ is hydrogen or lower alkyl; or                -   R₁₃ and R₁₂ combined are alkylene which together                    with the nitrogen atom to which they are attached                    form a 5- to 7-membered ring; or        -   W is absent;        -   R₉ is hydrogen, optionally substituted C₁-C₇ alkyl,            cycloalkyl, aryl or heterocyclyl; or        -   R₉ and R₁₀ combined are alkylene which together with the            nitrogen atom to which they are attached form a 5- to            7-membered ring;            or an enantiomer thereof; or an enantiomeric mixture            thereof; or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the B group having the formula

wherein

-   -   R₁ is hydrogen, halogen, cyano, trifluoromethyl, alkoxy,        alkylthio or carboxy;    -   R₂ is absent;    -   R₅ is hydrogen or lower alkyl;    -   R₉ is hydrogen, optionally substituted C₁-C₇ alkyl, cycloalkyl,        aryl or heterocyclyl;    -   R₁₀ is hydrogen or lower alkyl; or    -   R₁₀ is —C(O)R₁₁, —C(O)OR₁₁, or —C(O)NR₁₂R₁₃ in which        -   R₁₁ and R₁₂ are, independently from each other, optionally            substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or            heteroaralkyl;        -   R₁₃ is hydrogen or lower alkyl; or        -   R₁₃ and R₁₂ combined are alkylene which together with the            nitrogen atom to which they are attached form a 5- to            7-membered ring; or    -   R₁₀ and R₉ combined are alkylene which together with the        nitrogen atom to which they are attached form a 5- to 7-membered        ring;        or an enantiomer thereof; or an enantiomeric mixture thereof; or        a pharmaceutically acceptable salt thereof.

Preferred are the compounds of formula (IA) in the B group wherein

-   -   Q combined together with the carbon and nitrogen atoms to which        it is attached form a 5- to 6-membered monocyclic heteroaromatic        ring which is selected from the group consisting of

or an enantiomer thereof; or an enantiomeric mixture thereof; or apharmaceutically acceptable salt thereof.

Preferred are also the compounds in the A group, designated as the Cgroup, wherein

-   -   Q combined together with the carbon and nitrogen atoms to which        it is attached form a 5- to 6-membered monocyclic heteroaromatic        ring which is selected from the group consisting of

-   -   R₆ and R₅ combined are alkylene which together with the nitrogen        atom to which they are attached form a 4- to 7-membered ring        which may be optionally substituted, or may contain 1 to 3 other        heteroatoms selected from oxygen, nitrogen and sulfur, or may be        part of another ring;        or an enantiomer thereof; or an enantiomeric mixture thereof; or        a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the C group having the formula

wherein

-   -   R₁ is hydrogen, halogen, cyano, trifluoromethyl, alkoxy,        alkylthio or carboxy;    -   R₂ is absent;    -   R₁₄ is hydrogen, optionally substituted lower alkyl, cycloalkyl,        aryl, heteroaryl, aralkyl or heteroaralkyl; or    -   R₁₄ is —C(O)R₁₉, —C(O)OR₁₉, or —C(O)NR₂₀R₂₁ in which        -   R₁₉ and R₂₀ are, independently from each other, optionally            substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or            heteroaralkyl;        -   R₂₁ is hydrogen or lower alkyl; or        -   R₂₁ and R₂₀ combined are alkylene which together with the            nitrogen atom to which they are attached form a 5- to            7-membered ring;    -   R₁₅, R₁₆, R₁₇ and R₁₈ are, independently from each other,        hydrogen, halogen, hydroxy, alkoxy, free or esterified carboxy,        optionally substituted lower alkyl, cycloalkyl, aryl, aralkyl,        heteroaralkyl or heterocyclyl;        or an enantiomer thereof; or an enantiomeric mixture thereof; or        a pharmaceutically acceptable salt thereof.

Preferred are the compounds of formula (IB) in the C group wherein

-   -   Q combined together with the carbon and nitrogen atoms to which        it is attached form a 5- to 6-membered monocyclic heteroaromatic        ring which is selected from the group consisting of

or an enantiomer thereof; or an enantiomeric mixture thereof; or apharmaceutically acceptable salt thereof.

Further preferred are the compounds of formula (IB) in the C groupwherein

-   -   R₁₄ is methyl;        or an enantiomer thereof; or an enantiomeric mixture thereof; or        a pharmaceutically acceptable salt thereof.

Further preferred are also the compounds of formula (IB) in the C groupwherein

-   -   R₁₄, R₁₅, R₁₆, R₁₇ and R₁₈ are, independently from each other,        hydrogen or methyl; or an enantiomer thereof; or an enantiomeric        mixture thereof; or a pharmaceutically acceptable salt thereof.

Preferred are also the compounds in the C group having the formula

wherein

-   -   R₁ is hydrogen, halogen, cyano, trifluoromethyl, alkoxy,        alkylthio or carboxy;    -   R₂ is absent;    -   R₂₂ is hydrogen, optionally substituted lower alkyl, cycloalkyl,        aryl, heteroaryl, aralkyl or heteroaralkyl; or    -   R₂₂ is —C(O)R₁₉, —C(O)OR₁₉, or —C(O)NR₂₀R₂₁ in which        -   R₁₉ and R₂₀ are, independently from each other, optionally            substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or            heteroaralkyl;        -   R₂₁ is hydrogen or lower alkyl; or        -   R₂₁ and R₂₀ combined are alkylene which together with the            nitrogen atom to which they are attached form a 5- to            7-membered ring;    -   R₂₃, R₂₄, R₂₅ and R₂₆ are, independently from each other,        hydrogen, halogen, hydroxy, alkoxy, free or esterified carboxy,        optionally substituted lower alkyl, cycloalkyl, aryl, aralkyl,        heteroaralkyl or heterocyclyl; or    -   R₂₂ and R₂₅ combined are alkylene which together with the        nitrogen and carbon atoms to which they are attached form a 4-        to 7-membered ring; or    -   R₂₅ and R₂₆ combined are alkylene which together with the carbon        atom to which they are attached form a 3- to 7-membered ring;        or an enantiomer thereof; or an enantiomeric mixture thereof; or        a pharmaceutically acceptable salt thereof.

Preferred are the compounds of formula (IC) in the C group wherein

-   -   Q combined together with the carbon and nitrogen atoms to which        it is attached form a 5- to 6-membered monocyclic heteroaromatic        ring which is selected from the group consisting of

or an enantiomer thereof; or an enantiomeric mixture thereof; or apharmaceutically acceptable salt thereof.

Preferred are also the compounds in the A group, designated as the Dgroup, wherein

-   -   Q combined together with the carbon and nitrogen atoms to which        it is attached form a 9- to 10-membered bicyclic heterocycle        which is selected from the group consisting of

-   -   R₅ is hydrogen or lower alkyl;    -   R₆ is —(CR₇R₈)_(m)—W—R₉ in which        -   R₇ and R₈ are hydrogen;        -   m is an integer from 2 to 5;        -   W is —NR₁₀— in which            -   R₁₀ is hydrogen or lower alkyl; or            -   R₁₀ is —C(O)R₁₁, —C(O)OR₁₁, or —C(O)NR₁₂R₁₃ in which                -   R₁₁ and R₁₂ are, independently from each other,                    optionally substituted alkyl, cycloalkyl, aryl,                    heteroaryl, aralkyl or heteroaralkyl;                -   R₁₃ is hydrogen or lower alkyl; or                -   R₁₃ and R₁₂ combined are alkylene which together                    with the nitrogen atom to which they are attached                    form a 5- to 7-membered ring; or        -   W is absent;        -   R₉ is hydrogen, optionally substituted C₁-C₇ alkyl,            cycloalkyl, aryl or heterocyclyl; or        -   R₉ and R₁₀ combined are alkylene which together with the            nitrogen atom to which they are attached form a 5- to            7-membered ring;            or an enantiomer thereof; or an enantiomeric mixture            thereof; or a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the D group having the formula

wherein

-   -   R₁ is hydrogen, halogen, cyano, trifluoromethyl, alkoxy,        alkylthio or carboxy;    -   R₂ is absent;    -   R₅ is hydrogen or lower alkyl;    -   R₉ is hydrogen, optionally substituted C₁-C₇ alkyl, cycloalkyl,        aryl or heterocyclyl;    -   R₁₀ is hydrogen or lower alkyl; or    -   R₁₀ is —C(O)R₁₁, —C(O)OR₁₁, or —C(O)NR₁₂R₁₃ in which        -   R₁₁ and R₁₂ are, independently from each other, optionally            substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or            heteroaralkyl;        -   R₁₃ is hydrogen or lower alkyl; or        -   R₁₃ and R₁₂ combined are alkylene which together with the            nitrogen atom to which they are attached form a 5- to            7-membered ring; or    -   R₁₀ and R₉ combined are alkylene which together with the        nitrogen atom to which they are attached form a 5- to 7-membered        ring;        or an enantiomer thereof; or an enantiomeric mixture thereof; or        a pharmaceutically acceptable salt thereof.

Preferred are the compounds of formula (IA) in the D group wherein

-   -   Q combined together with the carbon and nitrogen atoms to which        it is attached form a 9- to 10-membered bicyclic heterocycle        which is selected from the group consisting of

or an enantiomer thereof; or an enantiomeric mixture thereof; or apharmaceutically acceptable salt thereof.

Preferred are also the compounds in the A group, designated as the Egroup, wherein

-   -   Q combined together with the carbon and nitrogen atoms to which        it is attached form a 9- to 10-membered bicyclic heterocycle        which is selected from the group consisting of

-   -   R₆ and R₅ combined are alkylene which together with the nitrogen        atom to which they are attached form a 4- to 7-membered ring        which may be optionally substituted, or may contain 1 to 3 other        heteroatoms selected from oxygen, nitrogen and sulfur, or may be        part of another ring;        or an enantiomer thereof; or an enantiomeric mixture thereof; or        a pharmaceutically acceptable salt thereof.

Preferred are the compounds in the E group having the formula

wherein

-   -   R₁ is hydrogen, halogen, cyano, trifluoromethyl, alkoxy,        alkylthio or carboxy;    -   R₂ is absent;    -   R₁₄ is hydrogen, optionally substituted lower alkyl, cycloalkyl,        aryl, heteroaryl, aralkyl or heteroaralkyl; or    -   R₁₄ is —C(O)R₁₉, —C(O)OR₁₉, or —C(O)NR₂₀R₂₁ in which        -   R₁₉ and R₂₀ are, independently from each other, optionally            substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or            heteroaralkyl;        -   R₂₁ is hydrogen or lower alkyl; or        -   R₂₁ and R₂₀ combined are alkylene which together with the            nitrogen atom to which they are attached form a 5- to            7-membered ring;    -   R₁₅, R₁₆, R₁₇ and R₁₈ are, independently from each other,        hydrogen, halogen, hydroxy, alkoxy, free or esterified carboxy,        optionally substituted lower alkyl, cycloalkyl, aryl, aralkyl,        heteroaralkyl or heterocyclyl;        or an enantiomer thereof; or an enantiomeric mixture thereof; or        a pharmaceutically acceptable salt thereof.

Preferred are the compounds of formula (IB) in the E group wherein

-   -   Q combined together with the carbon and nitrogen atoms to which        it is attached form a 9- to 10-membered bicyclic heterocycle        which is selected from the group consisting of

or an enantiomer thereof; or an enantiomeric mixture thereof; or apharmaceutically acceptable salt thereof.

Further preferred are the compounds of formula (IB) in the E groupwherein

-   -   R₁₄ is methyl;        or an enantiomer thereof; or an enantiomeric mixture thereof; or        a pharmaceutically acceptable salt thereof.

Further preferred are also the compounds of formula (IB) in the E groupwherein

-   -   R₁₄, R₁₅, R₁₆, R₁₇ and R₁₈ are, independently from each other,        hydrogen or methyl;        or an enantiomer thereof; or an enantiomeric mixture thereof; or        a pharmaceutically acceptable salt thereof.

Preferred are also the compounds in the E group having the formula

wherein

-   -   R₁ is hydrogen, halogen, cyano, trifluoromethyl, alkoxy,        alkylthio or carboxy;    -   R₂ is absent;    -   R₂₂ is hydrogen, optionally substituted lower alkyl, cycloalkyl,        aryl, heteroaryl, aralkyl or heteroaralkyl; or    -   R₂₂ is —C(O)R₁₉, —C(O)OR₁₉, or —C(O)NR₂₀R₂₁ in which        -   R₁₉ and R₂₀ are, independently from each other, optionally            substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or            heteroaralkyl;        -   R₂₁ is hydrogen or lower alkyl; or        -   R₂₁ and R₂₀ combined are alkylene which together with the            nitrogen atom to which they are attached form a 5- to            7-membered ring;    -   R₂₃, R₂₄, R₂₅ and R₂₆ are, independently from each other,        hydrogen, halogen, hydroxy, alkoxy, free or esterified carboxy,        optionally substituted lower alkyl, cycloalkyl, aryl, aralkyl,        heteroaralkyl or heterocyclyl; or    -   R₂₂ and R₂₅ combined are alkylene which together with the        nitrogen and carbon atoms to which they are attached form a 4-        to 7-membered ring; or    -   R₂₅ and R₂₆ combined are alkylene which together with the carbon        atom to which they are attached form a 3- to 7-membered ring;        or an enantiomer thereof; or an enantiomeric mixture thereof; or        a pharmaceutically acceptable salt thereof.

Preferred are the compounds of formula (IC) in the E group wherein

-   -   Q combined together with the carbon and nitrogen atoms to which        it is attached form a 9- to 10-membered bicyclic heterocycle        which is selected from the group consisting of

or an enantiomer thereof; or an enantiomeric mixture thereof; or apharmaceutically acceptable salt thereof.

The compounds of the invention depending on the nature of thesubstituents possess one or more asymmetric centers. The resultingdiastereoisomers, optical isomers, i.e., enantiomers, and geometricisomers, and mixtures thereof, are encompassed by the instant invention.Preferred are the compounds of the present invention wherein thesubstituent at the carbon atom adjacent to the amide group attains theR-configuration.

Particular embodiments of the invention are:

-   3-Cyclopentyl-N-isoquinolin-1-yl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;-   3-Cyclopentyl-N-(1-methyl-1H-benzoimidazol-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;-   3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-[1,3,4]thiadiazol-2-yl-propionamide;-   3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-quinolin-2-yl-propionamide;-   N-(6-Chloro-pyridazin-3-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;-   3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-methyl-thiazol-2-yl)-propionamide;-   2-{3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazole-4-carboxylic    acid;-   2-[3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-propionylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic    acid tert-butyl ester;-   3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-propionamide;-   3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-propionamide;-   3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-pyrazin-2-yl-propionamide;-   3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-pyridin-2-yl-propionamide;-   3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide;-   3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-pyrimidin-2-yl-propionamide;-   3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-thiazol-2-yl-propionamide;    and-   6-[3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-propionylamino]-nicotinic    acid;    or an enantiomer thereof; or an enantiomeric mixture thereof; or a    pharmaceutically acceptable salt thereof.

Compounds of formula (I) may be prepared using methods well known in theart, e.g., according to Method A or Method B as outlined herein below.

Method A:

Compounds of formula (I) may be obtained by coupling an amine of theformula

or acid addition salts thereof, Wherein R₁′ and R₂′ represents R₁ andR₂, respectively, as defined herein above, or R₁′ and R₂′ are groupsconvertible to R₁ and R₂, respectively, with an activated derivative ofa carboxylic acid of the formula

wherein R₃ and R₄ have meanings as defined herein, and R₅′ and R₆′represents R₅ and R₆, respectively, as defined herein above, or R₅′ andR₆′ are groups convertible to R₆ and R₆, respectively, to afford acompound of the formula

wherein R₁′, R₂′, R₃, R₄, R₅′ and R₆′ have meanings as defined forformulae (II) and (III).

In the coupling reaction cited herein above, an activated derivative ofa carboxylic acid, e.g., those corresponding to carboxylic acids offormula (III), include acid chlorides, bromides and fluorides, mixedanhydrides, lower alkyl esters and activated esters thereof, and adductsformed with coupling agents, such as1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl),1-hydroxy benzotriazole (HOBt),O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate, benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphoniumhexafluorophosphate (PyBOP) and the like. Mixed anhydrides arepreferably such from pivalic acid, or lower alkyl hemiesters of carbonicacids, such as ethyl or isobutyl analogs. Activated esters include, forexample, succinimido, phthalimido or 4-nitrophenyl esters. The reactionof an activated derivative of a carboxylic acid, e.g., thosecorresponding to carboxylic acids of formula (III), with an amine, e.g.,those of formula (II), may be carried out in the presence of a base,such as pyridine, triethylamine (TEA), diisopropylethylamine (DIEA) orN-methylmorpholine (NMM) in an inert organic solvent, such asdichloromethane (DCM), N,N-dimethylformamide (DMF) or tetrahydrofuran(THF), or a mixture of solvents thereof. Carboxylic acids of formula(III) may be converted to their activated derivatives using methodsdescribed herein or according to methods generally known in the art,e.g., a carboxylic acid of formula (III) may be treated with achlorinating agent, such as thionyl chloride or oxalyl chloride, toafford a corresponding acid chloride thereof, or by the treatment of acoupling agent such as EDCl or HOBt, or a mixture of coupling agentsthereof.

Amines of formula (II) and carboxylic acids of formula (III) are known,or if they are novel they may be prepared using methods well known inthe art or as described herein in the illustrative Examples, ormodifications thereof. For example, compounds of formula (III) may beprepared by treating an ester of the formula

wherein R₄ has a meaning as defined herein above, and R is lower alkyl,preferably, methyl or ethyl, with chlorosulfonic acid to afford acompound of the formula

wherein R₄ and R have meanings as defined herein above, optionally inthe presence of an intrinsic organic solvent. Preferably, the reactionis carried out without an intrinsic organic solvent.

A compound of formula (V) may then be treated with an amine of theformulaR₆′—NH—R₅′  (VI),or an acid addition salt thereof, wherein R₅′ and R₆′ have meanings asdefined herein above, in the presence of a base, such as pyridine, TEA,DIEA or NMM, in an inert organic solvent, such as DCM, DMF or THF, or amixture of solvents thereof, to afford a compound of the formula

wherein R₄, R₅′, R₆′ and R have meanings as defined herein above.Preferably, the reaction is conducted at a temperature ranging fromabout −4° C. to room temperature (RT), more preferably, the reactiontemperature is about 0° C. Amines of formula (VI) are known, or if theyare novel they may be prepared using methods well known in the art or asdescribed herein in the illustrative Examples.

A resulting compound of formula (VII) may then be treated with a base,such as sodium hydride, lithium diisopropylamide (LDA) or lithiumbis(trimethylsilyl)amide (LHMDS), preferably LDA, followed by additionof an alkylating agent of the formulaR₃—(CH₂)-Lg  (VIII)wherein R₃ has a meaning as defined herein above, and Lg represents aleaving group, such as chloride, bromide, iodide, mesylate, tosylate ortriflate, preferably iodide ot triflate, to afford a compound of theformula

wherein R₃, R₄, R₅′, R₆′ and R have meanings as defined herein above.The alkylation step is preferably conducted in a polar organic solvent,such as THF, DMF, N-methylpyrrolidone (NMP),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyridone (DMPU) or1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMTP), or in amixture of solvents thereof.

A resulting compound of formula (IX) may then be hydrolyzed, e.g., inthe presence of an aqueous base such as sodium, lithium or potassiumhydroxide and an organic solvent such as THF or lower alcohol,preferably, methanol or ethanol, to afford a carboxylic acid of formula(III) wherein R₃, R₄, R₅′ and R₆′ have meanings as defined herein above.

A carboxylic acid of formula (III) may then be coupled with an amine offormula (II), or an acid addition salt thereof, under reactionconditions as described herein above to afford a compound of formula(I′) wherein R₁′, R₂′, R₃, R₄, R₅′ and R₆′ have meanings as definedherein above, e.g., via conversion of the acid to the corresponding acidchloride or in the presence of a coupling agent such as EDCl, HOBt orPyBOP, or a mixture of coupling agents thereof.

Alternatively, compounds of formula (I) may be prepared as outlinedherein below.

Method B:

Compounds of formula (I) may be obtained by reacting a compound of theformula

wherein R₃ and R₄ have meanings as defined herein above, and R₁′ and R₂′represents R₁ and R₂, respectively, as defined herein above, or R₁′ andR₂′ are a groups convertible to R₁ and R₂, respectively, with an amineof the formulaR₆′—NH—R₅′  (VI),or an acid addition salt thereof, wherein R₅′ and R₆′ have meanings asdefined herein above, in the presence of a base, such as pyridine, TEA,DIEA or NMM, in an inert organic solvent, such as DCM, DMF or THF, or amixture of solvents thereof, to afford a compound of the formula

wherein R₁′, R₂′, R₃, R₄, R₅′ and R₆′ have meanings as defined hereinabove.

Compounds of formula (X) may be prepared, e.g., by treating a compoundof the formula

wherein R₄ and R have meanings as defined herein above, with a base,such as sodium hydride, LDA or LHMDS, preferably LDA, followed byaddition of an alkylating agent of the formulaR₃—(CH₂)-Lg  (VIII)wherein R₃ has a meaning as defined herein above, and Lg represents aleaving group, such as chloride, bromide, iodide, mesylate, tosylate ortriflate, preferably iodide or triflate, to afford a compound of theformula

wherein R₃, R₄ and R have meanings as defined herein above. Thealkylation step is preferably conducted in a polar organic solvent, suchas THF, DMF, NMP, DMPU or DMTP, or in a mixture of solvents thereof.

A resulting compound of formula (XII) may then be hydrolyzed, e.g., inthe presence of an aqueous base, such as sodium, lithium or potassiumhydroxide and an organic solvent such as THF or lower alcohol,preferably, methanol or ethanol, to afford a carboxylic acid of theformula

wherein R₃ and R₄ have meanings as defined herein above.

A carboxylic acid of formula (XIII) may then be coupled with an amine offormula (II) under reaction conditions as described herein above toafford a compound of the formula

wherein R₁′, R₂′, R₃ and R₄ have meanings as defined herein above, e.g.,via conversion of the carboxylic acid to the corresponding acidchloride, or in the presence of a coupling agent, such as EDCl, HOBt orPyBOP, or a mixture of coupling agents thereof.

A resulting compound of formula (XIV) may then be converted to asulfonyl chloride derivative of formula (X) wherein R₁′, R₂′, R₃ and R₄have meanings as defined herein above, by reduction of the nitro groupto the amino group, e.g., using iron powder in the presence of a mixtureof acetic acid and a lower alcohol, such as ethanol, followed bydiazotization reaction and subsequent treatment with, e.g., sulfurdioxide in the presence of copper(II) chloride and acetic acid.

A resulting sulfonyl chloride derivative of formula (X) may then betreated with an amine of formula (VI), or an acid addition salt thereof,wherein R₅′ and R₆′ have meanings as defined herein above, underreaction conditions described herein above to afford a compound offormula (I′) wherein R₁′, R₂′, R₃, R₄, R₅′ and R₆′ have meanings asdefined herein above.

The processes described herein above may be conducted under inertatmosphere, preferably under nitrogen atmosphere.

In starting compounds and intermediates which are converted to thecompounds of the present invention in a manner described herein,functional groups present, such as amino, thiol, carboxyl and hydroxylgroups, are optionally protected by conventional protecting groups thatare common in preparative organic chemistry. Protected amino, thiol,carboxyl and hydroxyl groups are those that can be converted under mildconditions into free amino thiol, carboxyl and hydroxyl groups withoutthe molecular framework being destroyed or other undesired sidereactions taking place.

The purpose of introducing protecting groups is to protect thefunctional groups from undesired reactions with reaction componentsunder the conditions used for carrying out a desired chemicaltransformation. The need and choice of protecting groups for aparticular reaction is known to those skilled in the art and depends onthe nature of the functional group to be protected (hydroxyl group,amino group, etc.), the structure and stability of the molecule of whichthe substituent is a part and the reaction conditions.

Well-known protecting groups that meet these conditions and theirintroduction and removal are described, e.g., in McOmie, “ProtectiveGroups in Organic Chemistry”, Plenum Press, London, N.Y. (1973); andGreene and Wuts, “Protective Groups in Organic Synthesis”, John Wileyand Sons, Inc., NY (1999).

The above-mentioned reactions are carried out according to standardmethods, in the presence or absence of diluent, preferably, such as areinert to the reagents and are solvents thereof, of catalysts, condensingor said other agents, respectively and/or inert atmospheres, at lowtemperatures, RT or elevated temperatures, preferably at or near theboiling point of the solvents used, and at atmospheric orsuper-atmospheric pressure. The preferred solvents, catalysts andreaction conditions are set forth in the appended illustrative Examples.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known per se.

The invention also relates to any novel starting materials,intermediates and processes for their manufacture.

Depending on the choice of starting materials and methods, the newcompounds may be in the form of one of the possible isomers or mixturesthereof, for example, as substantially pure geometric (cis or trans)isomers, diastereomers, optical isomers (enantiomers, antipodes),racemates or mixtures thereof. The aforesaid possible isomers ormixtures thereof are within the purview of this invention.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure geometricor optical isomers, diastereomers, racemates, for example, bychromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediate, e.g., acidsof formulae (III) and (XIII), can be resolved into the optically pureisomers by known methods, e.g., by separation of the diastereomericsalts thereof, obtainable with an optically active acid or base andliberating the optically active acidic or basic compound, respectively,e.g., acids of formulae (III) and (XIII) can be resolved using opticallyactive 1-phenylethylamine. Similarly, the compounds of the instantinvention having a basic moiety may be resolved into their opticalisomers, e.g., by fractional crystallization of a salt formed with anoptically active acid, e.g., tartaric acid, dibenzoyl tartaric acid,diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelic acid,malic acid or camphor-10-sulfonic acid. Racemic products can also beresolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent. Alternatively, opticallypure isomers of compounds of the present invention may be obtained byemploying chiral reagents. For example, an optical isomer, preferablythe R isomer, of a compound of the present invention may be preparedemploying chiral auxiliaries such as the Evans auxiliary.

Finally, compounds of the invention are either obtained in the freeform, or in a salt form thereof, preferably, in a pharmaceuticallyacceptable salt form thereof, or as a prodrug derivative thereof.

Compounds of the instant invention which contain acidic groups may beconverted into salts with pharmaceutically acceptable bases. Such saltsinclude alkali metal salts, like sodium, lithium and potassium salts;alkaline earth metal salts, like calcium and magnesium salts; ammoniumsalts with organic bases, e.g., trimethylamine salts, diethylaminesalts, tris(hydroxymethyl)methylamine salts, dicyclohexylamine salts andN-methyl-D-glucamine salts; salts with amino acids like arginine, lysineand the like. Salts may be formed using conventional methods,advantageously in the presence of an ethereal or alcoholic solvent, suchas a lower alkanol. From the solutions of the latter, the salts may beprecipitated with ethers, e.g., diethyl ether. Resulting salts may beconverted into the free compounds by treatment with acids. These orother salts can also be used for purification of the compounds obtained.

Compounds of the invention, in general, may be converted into acidaddition salts, especially pharmaceutically acceptable salts. These areformed, e.g., with inorganic acids, such as mineral acids, e.g.,sulfuric acid, phosphoric or hydrohalic acid, or with organic carboxylicacids, such as (C₁₋₄)alkanecarboxylic acids which, e.g., areunsubstituted or substituted by halogen, e.g., acetic acid, such assaturated or unsaturated dicarboxylic acids, e.g., oxalic, succinic,maleic or fumaric acid, such as hydroxycarboxylic acids, e.g., glycolic,lactic, malic, tartaric or citric acid, such as amino acids, e.g.,aspartic or glutamic acid, or with organic sulfonic acids, such as(C₁₋₄)alkylsulfonic acids, e.g., methanesulfonic acid; or arylsulfonicacids which are unsubstituted or substituted (for example by halogen).Preferred are salts formed with hydrochloric acid, maleic acid andmethanesulfonic acid.

Prodrug derivatives of any compound of the invention are derivatives ofsaid compounds which following administration release the parentcompound in vivo via some chemical or physiological process, e.g., aprodrug on being brought to the physiological pH or through enzymeaction is converted to the parent compound. Exemplary prodrugderivatives are, e.g., esters of free carboxylic acids and S-acyl andO-acyl derivatives of thiols, alcohols or phenols, wherein acyl has ameaning as defined herein. Preferred are pharmaceutically acceptableester derivatives convertible by solvolysis under physiologicalconditions to the parent carboxylic acid. Such ester derivativesinclude, but are not limited to, lower alkyl esters, cycloalkyl esters,lower alkenyl esters, benzyl esters, mono- or di-substituted lower alkylesters, such as the ω-(amino, mono- or di-lower alkylamino, carboxy,lower alkoxycarbonyl)-lower alkyl esters, the α-(lower alkanoyloxy,lower alkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters,such as the pivaloyloxymethyl ester and others conventionally used inthe art.

In view of the close relationship between the free compounds, theprodrug derivatives and the compounds in the form of their salts,whenever a compound is referred to in this context, a prodrug derivativeand a corresponding salt is also intended, provided such is possible orappropriate under the circumstances.

The compounds, including their salts, can also be obtained in the formof their hydrates, or include other solvents used for theircrystallization.

As described herein above, the compounds of the present invention may beemployed for the treatment of conditions mediated by glucokinaseactivity. Such compounds may thus be employed therapeutically for thetreatment of impaired glucose tolerance, type 2 diabetes and obesity.

The present invention further provides pharmaceutical compositionscomprising a therapeutically effective amount of a pharmacologicallyactive compound of the instant invention, alone or in combination withone or more pharmaceutically acceptable carriers.

The pharmaceutical compositions according to the invention are thosesuitable for enteral, such as oral or rectal; transdermal and parenteraladministration to mammals, including man, for the treatment ofconditions mediated by glucokinase activity. Such conditions includeimpaired glucose tolerance, type 2 diabetes and obesity.

Thus, the pharmacologically active compounds of the invention may beemployed in the manufacture of pharmaceutical compositions comprising aneffective amount thereof in conjunction or admixture with excipients orcarriers suitable for either enteral or parenteral application.Preferred are tablets and gelatin capsules comprising the activeingredient together with:

-   a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol,    cellulose and/or glycine;-   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or    calcium salt and/or polyethyleneglycol; for tablets also-   c) binders, e.g., magnesium aluminum silicate, starch paste,    gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose    and or polyvinylpyrrolidone; if desired-   d) disintegrants, e.g., starches, agar, alginic acid or its sodium    salt, or effervescent mixtures; and/or-   e) absorbants, colorants, flavors and sweeteners.

Injectable compositions are preferably aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions.

Said compositions may be sterilized and/or contain adjuvants, such aspreserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure and/or buffers. Inaddition, they may also contain other therapeutically valuablesubstances. Said compositions are prepared according to conventionalmixing, granulating or coating methods, respectively, and contain about0.1-75%, preferably about 1-50%, of the active ingredient.

Suitable formulations for transdermal application include atherapeutically effective amount of a compound of the invention withcarrier. Advantageous carriers include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host.Characteristically, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing the compoundoptionally with carriers, optionally a rate controlling barrier todeliver the compound of the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

Accordingly, the present invention provides pharmaceutical compositionsas described above for the treatment of conditions mediated byglucokinase activity, preferably, impaired glucose tolerance, type 2diabetes and obesity.

The pharmaceutical compositions may contain a therapeutically effectiveamount of a compound of the invention as defined above, either alone orin a combination with another therapeutic agent, e.g., each at aneffective therapeutic dose as reported in the art. Such therapeuticagents include:

-   a) anti-diabetic agents, such as insulin, insulin derivatives and    mimetics; insulin secretagogues such as the sulfonylureas, e.g.,    Glipizide, glyburide and Amaryl; insulinotropic sulfonylurea    receptor ligands such as meglitinides, e.g., nateglinide and    repaglinide; thiazolidone derivatives such as glitazones, e.g.,    pioglitazone and rosiglitazone; protein tyrosine phosphatase-1B    (PTP-1B) inhibitors such as PTP-112; GSK3 (glycogen synthase    kinase-3) inhibitors such as SB-517955, SB-4195052, SB-216763,    N,N-57-05441 and N,N-57-05445; RXR ligands such as GW-0791 and    AGN-194204; sodium-dependent glucose co-transporter inhibitors such    as T-1095; glycogen phosphorylase A inhibitors such as BAY R3401;    biguanides such as metformin; alpha-glucosidase inhibitors such as    acarbose; GLP-1 (glucagon like peptide-1), GLP-1 analogs such as    Exendin-4 and GLP-1 mimetics; modulators of PPARs (peroxisome    proliferator-activated receptors), e.g., non-glitazone type PPARγ    agonists such as N-(2-benzoylphenyl)-L-tyrosine analogues, e.g.    GI-262570, and JTT501; DPPIV (dipeptidyl peptidase IV) inhibitors    such as LAF237, MK-0431, saxagliptin and GSK23A; SCD-1 (stearoyl-CoA    desaturase-1) inhibitors; DGAT1 and DGAT2 (diacylglycerol    acyltransferase 1 and 2) inhibitors; ACC2 (acetyl CoA carboxylase 2)    inhibitors; and breakers of AGE (advanced glycation end products);-   b) anti-dyslipidemic agents such as 3-hydroxy-3-methyl-glutaryl    coenzyme A (HMG-CoA) reductase inhibitors, e.g., lovastatin,    pitavastatin, simvastatin, pravastatin, cerivastatin, mevastatin,    velostatin, fluvastatin, dalvastatin, atorvastatin, rosuvastatin and    rivastatin; HDL increasing compounds such as cholesterol ester    transfer protein (CETP) inhibitors, e.g., JTT705; Apo-A1 analogs and    mimetics; squalene synthase inhibitors; FXR (farnesoid X receptor)    and LXR (liver X receptor) ligands; cholestyramine; fibrates;    nicotinic acid; and aspirin;-   c) anti-obesity agents such as phentermine, leptin, bromocriptine,    dexamphetamine, amphetamine, fenfluramine, dexfenfluramine,    sibutramine, orlistat, dexfenfluramine, mazindol, phentermine,    phendimetrazine, diethylpropion, fluoxetine, bupropion, topiramate,    diethylpropion, benzphetamine, phenylpropanolamine, ecopipam,    ephedrine, and pseudoephedrine; cholesterol absorption modulators    such as ZETIA® and KT6-971; and cannabinoid receptor antagonists    such as rimonabant; and-   d) anti-hypertensive agents, e.g., loop diuretics such as ethacrynic    acid, furosemide and torsemide; angiotensin converting enzyme (ACE)    inhibitors such as benazepril, captopril, enalapril, fosinopril,    lisinopril, moexipril, perinodopril, quinapril, ramipril and    trandolapril; inhibitors of the Na—K-ATPase membrane pump such as    digoxin; neutralendopeptidase (NEP) inhibitors; ACE/NEP inhibitors    such as omapatrilat, sampatrilat and fasidotril; angiotensin II    antagonists such as candesartan, eprosartan, irbesartan, losartan,    telmisartan and valsartan, in particular valsartan; renin inhibitors    such as ditekiren, zankiren, terlakiren, aliskiren, RO 66-1132 and    RO-66-1168; β-adrenergic receptor blockers such as acebutolol,    atenolol, betaxolol, bisoprolol, metoprolol, nadolol, propranolol,    sotalol and timolol; inotropic agents such as digoxin, dobutamine    and milrinone; calcium channel blockers such as amlodipine,    bepridil, diltiazem, felodipine, nicardipine, nimodipine,    nifedipine, nisoldipine and verapamil; aldosterone receptor    antagonists such as eplerenone; and aldosterone synthase inhibitors    such as anastrazole and fadrazole.

Other specific anti-diabetic compounds are described by Patel Mona inExpert Opin Investig Drugs, 2003, 12(4), 623-633, in the FIGS. 1 to 7,which are herein incorporated by reference. A compound of the presentinvention may be administered either simultaneously, before or after theother active ingredient, either separately by the same or differentroute of administration or together in the same pharmaceuticalformulation.

The structure of the therapeutic agents identified by code numbers,generic or trade names may be taken from the actual edition of thestandard compendium “The Merck Index” or from databases, e.g., PatentsInternational (e.g. IMS World Publications). The corresponding contentthereof is hereby incorporated by reference.

Accordingly, the present invention provides pharmaceutical compositionscomprising a therapeutically effective amount of a compound of theinvention in combination with a therapeutically effective amount ofanother therapeutic agent, preferably selected from anti-diabetics,hypolipidemic agents, anti-obesity agents or anti-hypertensive agents,most preferably from antidiabetics or hypolipidemic agents as describedabove.

The present invention further relates to pharmaceutical compositions asdescribed above for use as a medicament.

The present invention further relates to use of pharmaceuticalcompositions or combinations as described above for the preparation of amedicament for the treatment of conditions mediated by glucokinaseactivity, preferably, impaired glucose tolerance, type 2 diabetes andobesity.

Thus, the present invention also relates to a compound of formula (I)for use as a medicament; to the use of a compound of formula (I) for thepreparation of a pharmaceutical composition for the prevention and/ortreatment of conditions mediated by glucokinase activity, and to apharmaceutical composition for use in conditions mediated by glucokinaseactivity comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, in association with a pharmaceuticallyacceptable diluent or carrier therefore.

The present invention further provides a method for the preventionand/or treatment of conditions mediated by glucokinase activity, whichcomprises administering a therapeutically effective amount of a compoundof the present invention.

A unit dosage for a mammal of about 50-70 kg may contain between about 1mg and 1000 mg, advantageously between about 5-500 mg of the activeingredient. The therapeutically effective dosage of active compound isdependent on the species of warm-blooded animal (mammal), the bodyweight, age and individual condition, on the form of administration, andon the compound involved.

In accordance with the foregoing the present invention also provides atherapeutic combination, e.g., a kit, kit of parts, e.g., for use in anymethod as defined herein, comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, to be used concomitantly or insequence with at least one pharmaceutical composition comprising atleast another therapeutic agent, preferably selected from anti-diabeticagents, hypolipidemic agents, anti-obesity agents and anti-hypertensiveagents, or a pharmaceutically acceptable salt thereof. The kit maycomprise instructions for its administration.

Similarly, the present invention provides a kit of parts comprising: (i)a pharmaceutical composition of the invention; and (ii) a pharmaceuticalcomposition comprising a compound selected from an anti-diabetic, ahypolipidemic agent, an anti-obesity agent and an anti-hypertensiveagent, or a pharmaceutically acceptable salt thereof, in the form of twoseparate units of the components (i) to (ii).

Likewise, the present invention provides a method as defined abovecomprising co-administration, e.g., concomitantly or in sequence, of atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof, and a second drug substance,said second drug substance being an anti-diabetic, a hypolipidemicagent, an anti-obesity agent or an anti-hypertensive agent, e.g., asindicated above.

Preferably, a compound of the invention is administered to a mammal inneed thereof.

Preferably, a compound of the invention is used for the treatment of adisease which responds to modulation of the glucokinase activity.

Preferably, the condition associated with glucokinase activity isselected from impaired glucose tolerance, type 2 diabetes and obesity.

Finally, the present invention provides a method or use which comprisesadministering a compound of formula (I) in combination with atherapeutically effective amount of an anti-diabetic agent, ahypolipidemic agent, an anti-obesity agent or an anti-hypertensiveagent.

Ultimately, the present invention provides a method or use whichcomprises administering a compound of formula (I) in the form of apharmaceutical composition as described herein.

As used throughout the specification and in the claims, the term“treatment” embraces all the different forms or modes of treatment asknown to those of the pertinent art and in particular includespreventive, curative, delay of progression and palliative treatment.

The above-cited properties are demonstrable in vitro and in vivo testsusing advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. Said compounds can beapplied in vitro in the form of solutions, e.g., preferably aqueoussolutions, and in vivo either enterally, parenterally, advantageouslyintravenously, e.g., as a suspension or in aqueous solution. The dosagein vitro may range between about 10⁻² molar and 10⁻⁹ molarconcentrations. A therapeutically effective amount in vivo may rangedepending on the route of administration, between about 0.1 mg/kg and1000 mg/kg, preferably between about 1 mg/kg and 100 mg/kg.

The activity of compounds according to the invention may be assessed bythe following methods or methods well-described in the art:

For example, the glucokinase activation in vitro may be determined bymeasuring the activation of recombinant GST-GK by a compound of thepresent invention in the absence or the presence of GKRP, a 68,000 Daprotein inhibitor of GK. In these assays, formation ofglucose-6-phosphate is coupled directly to the formation of thio-NADH.GST-GK catalyzes the reaction of glucose and Mg-ATP to produceglucose-6-phosphate and ADP. Glucose-6-phosphate dehydrogenase (G6PDH)reduces thionicotinamide (thio-NAD) to thio-NADH. The assay measures theformation of thio-NADH at 405 nM.

The basic GK assay components are as follows: 25 mM HEPES (pH 7.1), 25mM KCl, 2.5 mM MgCl₂, 1 mM ATP (Sigma A-5394), 1 mM DTT, 1 mM thio-NAD(Sigma T-7375), 80 units/mL G6PDH (Sigma G-5885), 10 mM glucose and 110nM GST-GK. For assessing reversal of GK inhibition by GKRP, 20 μMFructose-6-phosphate (F-6-P) and 370 nM recombinant GKRP are added tothese assay components. Fructose-1-phosphate (F-1-P) at 1 μM is used asa control in the GK/GKRP assay. F-1-P reverses inhibition of GST-GK byGKRP.

The assay is done in standard, 96-well, round-bottom plates (Corning)and the total assay volume is 25 μL. Test compounds are serially dilutedinto 100% DMSO and 0.5 μL of diluted compound in 100% DMSO is added tothe assay plate. Assay reagents (24.5 μL) are added using a Zymarkrobotic platform. Buffer, containing HEPES, MgCl₂, KCl, thio-NAD, G6PDH,glucose and GST-GK, are added (5 μL) using the Zymark 8-channel handpipet. For the GK/GKRP assay, GKRP and F-6-P are also included. Thereaction is then initiated by adding 19.5 μL of buffer containing HEPES,MgCl₂, KCl, DTT and ATP using the Zymark Reagent AdditionStation/Reagent Addition Module. The plates are read kinetically over 10min at 25° C. using a SpectraMax Plus microplate spectrophotometer(Molecular Devices, Sunnyvale, Calif.) to monitor the increase inoptical density at 405 nm. The GK activity in wells containing testcompounds is compared with activity in DMSO control wells. Theconcentration of compound that produces a 50% increase in the activityof GK is calculated and expressed as EC₅₀. All of the compoundsdescribed in the Examples had an EC₅₀ value less than or equal to 200 μMand preferably less than 20 μM. Most preferable are compounds with EC₅₀less than 2 μM which exhibited at least a 2-fold increase in % GKactivation versus control.

The glucokinase activation in rat hepatocytes may be determined asfollows:

Hepatocytes are isolated by collagenase perfusion of the livers ofovernight-fasted male Harlen Sprague-Dawley rats (Charles RiverLaboratories, Raleigh, N.C.) as previously described (see Berry et al.,J. Cell Biol., Vol. 43, pp. 506-520 (1969)). The cells are washed threetimes each with 100 mL of glucose-free Dulbecco's Modified Eagle medium(DMEM, Gibco BRL) containing 5% fetal bovine serum (FBS) and thensuspended in glucose-free DMEM/5% FBS. Cells are plated in collagencoated 24-well plates (Becton Dickinson) at a density of 3×10⁵cells/well in 1 mL of William's Medium E (Sigma) supplemented with 5%FBS, and incubated at 37° C. in 5% CO₂/95% air. After cell attachment(˜4 h), the medium is replaced with serum-free DMEM containing 5 mMglucose and 10 nM dexamethasone (Sigma), and cells are cultured furtherfor 16-20 h prior to use.

The rate of glucose phosphorylation is determined by the release of ³H₂Ofrom [2-³H]glucose. The medium from the cultured hepatocytes is removed,and the cells are pre-incubated in 150 μL of fresh serum-free DMEMcontaining 5 mM glucose and compound (1, 10 and 30 μM) or DMSO for 3 hat 37° C. The final concentration of DMSO is 0.2%. The medium is thenremoved and 150 μL of a fresh mixture of DMEM/5 mM glucose containingcompound or DMSO, and 1 μCi of [2-³H]glucose (NEN) is added. As apositive control for stimulation of glucose phosphorylation, cells arepre-incubated in serum-free DMEM/5 mM glucose medium containing DMSO for3 h and then are incubated for 1 h in labeled glucose medium containing0.5 mM fructose/DMSO (precursor of F-1-P, AnalaR® from BDH). Allconditions are tested in quadruplicate where one well per plate received200 μL of the appropriate medium plus labeled glucose (instead of 150μL) of which 50 μL is immediately removed and placed in a 1.2 mLmicrofuge tube (Costar) containing 10 μL of 1 N HCl. This sample is usedas a 0-minute time point for determining background ³H₂O release(exchange values). Following the addition of the labeled glucose media,hepatocytes are incubated at 37° C. on a slow moving rocker for 1 h.

On termination of the incubation, 50 μL of the culture medium iscollected into microfuge tubes containing 10 μL of 1 N HCl, anddetermination of ³H₂O. The tubes are left uncapped and each is placedinside a 20 mL glass scintillation vial (Wheaton) containing 1.5 mL ofdeionized water. The vials are capped tightly and incubated at 37° C. ina dry incubator for 2 days (3H₂O from the reaction mixture willequilibrate with the water in the vial). A standard curve is generatedusing [³H]H₂O (NEN) to correct for exchange. 50 μL aliquots of serialdilutions of the labeled water are added to 10 μL of 1 N HCl andexchange is performed as described for the samples (typically,approximately 90% exchange is observed). The microfuge tubes are thenremoved from the vials carefully to minimize the removal of any waterfrom the vial and 18 mL of scintillation cocktail (Ready Safe, BeckmanCoulter) is then added to each vial. The ³H-label recovered from[2-³H]glucose in the water is determined using a Beckman Model LS500scintillation counter and the counts (minus the 0-time point) arecorrected for recovery of ³H₂O. The amount of glucose de-tritiated innanomoles/h per 10⁶ cells is calculated, and the results are expressedas percent increase over the DMSO control.

The glucokinase activation in vivo may be determined as follows:

Male C57BL mice (Jackson Lab, Bar Harbor, Me.) are housed 2 per cage ina reversed light cycle room (light on from 8:00 p.m. to 8:00 a.m.) andgiven access to food and water ad libitum. To induce DIO, the mice aregiven a high fat diet (D12492 with 60% caloric intake from fat, ResearchDiets, New Brunswick, N.J.) from 4 weeks of age and maintained on thediet before being used. The DIO mice are used at 25 weeks of age. On theday of the study, animals are fasted at 7:30 a.m. Body weightmeasurement and basal blood sample collection are conducted at 10:00a.m. Plasma glucose values are then determined. Animals are assignedinto five groups (n=7/group) with the means of plasma glucose matchedamong the groups. At 10:30 a.m. animals are dosed with vehicle (water)or compound in vehicle with a dose volume of 5 ml/kg. The test compoundis given at 3, 10, 30, or 100 mg/kg. One hour after vehicle or compounddosing, a blood sample (at 0 min) is taken followed by an oral glucosetolerance test (OGTT) at 1 g/kg (20% glucose in water) and a dose volumeof 5 ml/kg. Blood samples are collected at 30, 60 and 120 min followingthe glucose administration. The animals are refed after the OGTT. Bloodsamples are taken via tail bleeding. Plasma glucose concentrations aredetermined using a glucose meter (Ascensia Elite, Bayer Corp.,Mishawaka, Ind.). Blood samples are collected in tubes (MicrovetteCB300, Aktiengesellschaft & Co., Numbrecht, Germany) which contain EDTA(ethylene diaminetetraacetic acid) to prevent blood clotting. Afterblood sample collection, the tubes are kept on ice before beingcentrifuged. Plasma portion of the blood samples is obtained bycentrifugation at 10,000×g for 10 min at 4° C. and then stored at −80°C. Plasma insulin levels are determined by Luminex assay using MouseEndocrine Lincoplex kit (Linco Research, Inc., St. Charles, Mo.). Dataare reported as means±SEM. Statistical analysis is performed using aone-way or two-way analysis of variance (ANOVA) followed by a Tukeypost-hoc test to compare the difference among the groups. Statisticalsignificance is accepted at the level of p<0.05.

The following Examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. If not mentionedotherwise, all evaporations are performed under reduced pressure,preferably between about 50 mmHg and 100 mmHg. The structure of finalproducts, intermediates and starting materials is confirmed by standardanalytical methods, e.g., microanalysis, melting point (m.p.) andspectroscopic characteristics, e.g., MS, IR and NMR. Abbreviations usedare those conventional in the art.

EXAMPLE 13-Cyclopentyl-N-isoquinolin-1-yl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamidehydrochloride

A. 1-(4-Bromo-benzenesulfonyl)-4-methyl-piperazine

N-methylmorpholine (60 g, 65 mL, 0.6 mol) is dissolved in DCM (100 mL),to which 1-methylpiperazine (30.5 g, 0.3 mol) is added. The reaction iscooled to 0° C., after which a solution of 4-bromo-benzenesulfonylchloride (75.8 g, 0.296 mol) in DCM (100 mL) is added dropwise. Thereaction is allowed to warm to RT overnight. The reaction mixture isthen concentrated and water (1 L) is added. The solids that are formedare filtered and the filtrate is extracted with EtOAc (500 mL). Theorganic layer is washed with saturated brine, dried over MgSO₄, filteredand concentrated to afford1-(4-bromo-benzenesulfonyl)-4-methyl-piperazine as a pale yellow solid:LC/MS 321.0 (M+1); ¹H NMR (400 MHz, CDCl3) δ 2.3 (s, 3 H) 2.5 (m, 4 H)3.0 (m, 4 H) 7.6 (dt, J=8.8, 2.0 Hz, 2 H) 7.7 (dt, J=8.8, 2.1 Hz, 2 H).

B. [4-(4-Methyl-piperazine-1-sulfonyl)-phenyl]-acetic Acid Ethyl Ester

The title A compound, 1-(4-bromo-benzenesulfonyl)-4-methyl-piperazine(5.00 g, 15.663 mmol), ethyl acetoacetate (2.97 mL, 23.495 mmol),2-(di-tert-butylphosphino)-2-methyl biphenyl (98 mg, 0.313 mmol),palladium acetate (105 mg, 0.157 mmol) and potassium phosphate (9.97 g,46.989 mmol) are charged to a flask. Toluene (60 mL) is added. Thereaction is heated at 90° C. overnight, then cooled to RT. The reactionmixture is poured onto ethyl acetate and water. The organic layer isdried over anhydrous sodium sulfate, filtered and concentrated to afforda brown oil. This is chromatographed using 0→20% methanol in ethylacetate to afford [4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-aceticacid ethyl ester as a tan solid which contains ˜8% of the acylatedmaterial: LC/MS 327.1 (M+1); ¹H NMR (400 MHz, DMSO-D₆) δ 1.2 (t, J=7.1Hz, 3 H) 2.1 (s, 3 H) 2.3 (m, 4 H) 2.9 (d, J=4.3 Hz, 4 H) 3.8 (s, 2 H)4.1 (q, J=7.1 Hz, 2 H) 7.5 (d, J=8.3 Hz, 2 H) 7.6 (d, 7.7 (m, 2 H). C.3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionicAcid Ethyl ester

DIEA (0.742 g, 7.32 mmol) is dissolved in THF (10 mL) and cooled to −78°C., under an atmosphere of N₂. n-BuLi (2.5M in hexanes, 2.25 mL, 5.63mmol) is added to this slowly. The resulting solution is stirred at −78°C. for 15 min. A solution of the title B compound,[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester(1.84 g, 5.63 mmol) in THF/DMPU (10 mL/5 mL) is then added dropwise. Thereaction is then stirred at −78° C. for one hour. A solution ofcyclopentylmethyl iodide (1.18 g, 5.63 mmol) in THF/DMPU (10 mL/5 mL) isthen added dropwise and the reaction is allowed to warm to RT overnight.The reaction is then poured into saturated NH₄Cl solution and extractedwith EtOAc. The organic layer is dried over MgSO₄, filtered andconcentrated to afford a brown oil. This is purified by flashchromatography (0→2% EtOAc in MeOH) to afford3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionicacid ethyl ester as a brown oil: ¹H NMR (CDCl₃) δ 1.12 (m, 2H) 1.24 (m,3H) 1.50 (m, 2H) 1.60 (m, 3H) 1.76 (m, 2H) 2.08 (m, 2H) 2.27 (s, 3H)2.47 (s, 4H) 3.04 (s, 4H) 3.65 (m, 1H) 4.13 (m, 2H) 7.48 (m, 2H) 7.69(m, 2H); LC/MS 409.3 (M+1).

D. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionicAcid Hydrochloride

The title C compound,3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionicacid ethyl ester (1.98 g, 4.846 mmol) is dissolved in THF. To this isadded a solution of sodium hydroxide (94 mg, 4.846 mmol) in water. Thereaction is stirred at RT overnight, then concentrated to dryness. Theresulting solid is dissolved in 4 N hydrochloric acid in dioxane andstirred at RT for 30 min. Concentration affords3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionicacid hydrochloride salt containing one equivalent of sodium chloride:LC/MS 381.3 (M+1); ¹H NMR (400 MHz, DMSO-D₆) δ 1.1 (m, 2 H) 1.4 (m, 2 H)1.5 (m, 3 H) 1.7 (m, 3 H) 2.0 (ddd, J=13.3, 7.7, 7.6 Hz, 1 H) 2.7 (m, 5H) 3.1 (d, J=10.1 Hz, 2 H) 3.4 (d, J=12.1 Hz, 2 H) 3.7 (m, 3 H) 7.6 (d,J=8.3 Hz, 2 H) 7.7 (d, J=8.3 Hz, 2 H) 11.3 (s, 1 H).

E.3-Cyclopentyl-N-isoquinolin-1-yl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamideHydrochloride

The title D compound,3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionicacid hydrochloride (150 mg, 0.346 mmol) is slurried in DMF (3 mL) withTEA (97 μL, 0.692 mmol) and cooled to 0° C. After 45 min,isoquinolin-1-ylamine (50 mg, 0.346 mmol) in pyridine (1 mL) is addeddropwise. The reaction is allowed to stir and warm to RT overnight. Thereaction is diluted with ethyl acetate and water. The organic layer isseparated, dried over anhydrous sodium sulfate, filtered andconcentrated to afford a brown oil. Purification via flashchromatography using 0→2% methanol in ethyl acetate affords the pureproduct. This is dissolved in 1 M hydrochloric acid in ether and stirredat RT for 30 min, then concentrated. Dissolution in water followed bylyophilization affords3-cyclopentyl-N-isoquinolin-1-yl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide,hydrochloric salt as a yellow solid: LC/MS 507.4 (M+1), 505.5 (M−1); ¹HNMR (400 MHz, DMSO-D₆) δ 1.2 (m, 2 H) 1.5 (m, 2 H) 1.6 (m, 2 H) 1.7 (m,2 H) 1.8 (dd, J=13.3, 6.9 Hz, 2 H) 2.2 (dd, J=13.0, 7.5 Hz, 1 H) 2.7 (m,5 H) 2.9 (s, 1 H) 3.1 (s, 1 H) 3.4 (d, J=11.9 Hz, 2 H) 3.8 (d, J=12.4Hz, 2 H) 5.0 (s, 1 H) 7.8 (m, 2 H) 7.9 (m, 2 H) 8.0 (m, 2 H) 8.1 (t,J=7.6 Hz, 1 H) 8.2 (d, J=8.1 Hz, 1 H) 8.2 (d, J=6.6 Hz, 1 H) 9.0 (s, 1H) 11.1 (s, 1 H). EC₅₀ in primary enzyme assay 50 μM

EXAMPLE 2 Preparation of(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide

A. Phenylacetic Acid Ethyl Ester

A solution of phenylacetic acid (50 g, 0.36 mol) in ethanol (150 mL) istreated with catalytic amount of sulfuric acid (4 mL). The reactionmixture is refluxed for 4 h. The reaction is then concentrated in vacuo.The residue is dissolved in diethyl ether (300 mL) and washed withsaturated aqueous sodium bicarbonate solution (2×50 mL) and water (1×100mL). The organic layer dried over sodium sulfate filtered andconcentrated in vacuo to give phenylacetic acid ethyl ester as acolorless oil: ¹H NMR (400 MHz, CDCl₃) δ 1.2 (t, J=7.2, 3H), 3.6 (s,2H), 4.1 (q, J=7.2, 2H), 7.3 (m, 5H); MS 165 [M+1]⁺.

B. (4-Chlorosulfonyl-phenyl)-acetic Acid Ethyl Ester

To 160 mL of chlorosulfonic acid cooled to 0° C. under nitrogen is addedthe title A compound, phenylacetic acid ethyl ester (59 g, 0.35 mol)over a period of 1 h. Reaction temperature is brought to RT (28° C.),then stirred at ambient temperature for 18 h. The reaction is pouredonto ice, extracted with ethyl acetate, dried over MgSO4, filtered andevaporated to a yellow oil and used directly in the next step.

C. 4-(4-Ethoxycarbonylmethyl-benzenesulfonyl)-piperazine-1-carboxylicAcid Tert-butyl Ester

To a solution of N—BOC-piperazine (21.5 g, 0.114 mol) and DIEA (16.4 g,22 mL, 0.13 mol) in 250 mL of DCM cooled to 0° C. is added a solution ofthe title B compound, 4-chlorosulfonyl-phenyl)-acetic acid ethyl ester(30 g, 0.114 mol) in 50 mL of DCM within 30 min. The reaction mixturewas stirred at ambient temperature for 18 h, and then evaporated to acrude solid. The residue is treated with 200 mL of 1N HCl and extractedwith ethyl acetate. The combined organic layer is washed with brine,sat. sodium carbonate and then with brine, dried with MgSO4, filteredand evaporated to a yellow oil which crystallized upon standing. Thiscrude crystalline mass was recrystallized from MTBE to produce pure[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-acetic acid ethyl ester as awhite solid: ¹H NMR (400 MHz, CDCl₃) δ ppm 1.25 (t, 3 H, J=7.1 Hz) 1.4(s, 9 H) 3.0 (t, 4 H, J=5 Hz) 3.5 (t, 4 H, J=5 Hz) 3.7 (s, 2 H) 4.2 (q,J=7.1 Hz, 2 H) 7.5 (d, J=8.6 Hz, 2 H) 7.7 (d, 2 H, J=8.6 Hz) MS 399[M+1]⁺.

D.4-[4-(2-Cyclopentyl-1-ethoxycarbonyl-ethyl)-benzenesulfonyl]-piperazine-1-carboxylicAcid Tert-butyl Ester

LDA is freshly prepared from DIA (1.4 mL, 10.0 mol) and 3.7 mL (9.2mmol) of 2.5 M nBuLi/hexanes in 50 mL of THF at −78° C. under an inertatmosphere. Title compound C (3.6 g, 9.0 mmol) in 15 mL of anhydrous THFis added dropwise and stirred for 1 h before the freshly preparedtriflate of cyclopentylmethanol (2.5 g, 10.5 mmol) in 15 mL of THF isadded dropwise. The reaction is allowed to warm to ambient temperatureand then is quenched into 100 mL of 1N aqueous HCl. The mixture isextracted with ethyl acetate, washed with brine and the combined organiclayer dried over MgSO4, filtered and evaporated to afford product as awhite solid: ¹H NMR (400 MHz, DMSO-D6) δ ppm 1.06-1.15 (m, 2H) 1.1 (t, 3H, J=7.1 Hz) 1.3 (s, 9H) 1.4 (m, 2 H) 1.6 (m, 4 H) 1.7 (m, 2 H) 2.0 (m,1H) 2.8 (t, 4 H, 5 Hz) 3.4 (t, 4 H, J=5 Hz) 3.8 (t, 1 H J=8 Hz) 4.1 (q,2 H, J=7.1 Hz) 7.6 (d, 2 H, J=8.3 Hz) 7.7 (d, 2 H, J−=8.3 Hz) MS 493[M+1]⁺.

E. 3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionicAcid

To a solution of the title D compound,4-[4-(2-Cyclopentyl-1-ethoxycarbonyl-ethyl)-benzenesulfonyl]-piperazine-1-carboxylicacid tert-butyl ester (2.4 g, 5.1 mmol) in 25 mL of ethanol was addedsodium hydroxide (0.6 g, 15 mmol) and the mixture stirred at ambienttemperature for 15 h. The ethanol is then removed in vacuo at 45-50° C.and the residue dissolved in water (25 mL) and extracted with ether(1×40 mL). The aqueous layer is acidified to pH 5 with 3 N aqueoushydrochloric acid solution and subsequently extracted with ethylacetate. The combined organic layers were dried over MgSO4, filtered andevaporated to afford title compound E as a white solid: ¹H NMR (400 MHz,DMSO-D6) δ ppm 1.06-1.15 (m, 2H) 1.3 (s, 9 H) 1.4 (m, 2 H) 1.6 (m, 3 H)1.7 (m, 2 H) 2.0 (ddd, J=14.2, 7.0, 6.8 Hz, 1 H) 2.8 (t, 4 H, J=5 Hz)3.4 (t, 4H, J=5 Hz) 3.68 (t, 1H, J=8 Hz) 7.6 (d, J=8.3 Hz, 2 H) 7.7 (d,2 H, J=8.3 Hz)

MS 421 [M—CO2]⁻.

F.4-{4-[1-(5-Bromo-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-2-cyclopentyl-ethyl]-benzenesulfonyl}-piperazine-1-carboxylicAcid Tert-butyl Ester

To a mixture of title compound E,3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionicacid (5.0 g, 10.7 mmol), HOBt (2.8 g, 20.7 mmol) and EDC (4.1 g, 20.7mmol) in 100 mL of DMF at 0° C. was added 5.3 mL of DIEA, and themixture is stirred for 30 min prior to addition of5-Bromo-thiazolo[5,4-b]pyridin-2-yl amine (2.4 g, 10.7 mmol). Thereaction mixture is stirred at ambient temperature for 18 h and thenquenched into brine and extracted with ethyl acetate. The combinedextracts were washed with 1N NaOH, brine and then dried over MgSO4.Filtration and evaporation then afforded a brownish foam which ispurified by chromatography over silica to provide title compound F: ¹HNMR (400 MHz, DMSO-D6) δ ppm 1.06-1.17 (m, 2 H) 1.3 (s, 9 H) 1.37-1.46(m, 2 H) 1.5-1.6 (m, 4 H) 1.68 (m, 2H) 1.77-1.84 (m, 1H) 2.8 (m, 4 H)3.4 (m, 4H) 4.1 (t, 1H J=8.4 Hz) 7.65-7.68 (m, 4 H) 7.72 (d, 1H, J=8.5Hz) 9.04 (d, 1H, J=8.5 Hz) 12.9 (m, 1H); δ 1. MS 680 [M+1]⁺, 678[M−1]⁻,

G.4-{4-[2-Cyclopentyl-1-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperazine-1-carboxylicAcid Tert-butyl Ester

To title compound F,4-{4-[1-(5-Bromo-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-2-cyclopentyl-ethyl]-benzenesulfonyl}-piperazine-1-carboxylicacid tert-butyl ester (0.1 g, 0.148 mmol) in a microwave vial was addedPd₂ dba₃ (0.013 g, 0.0148 mmol), Xanphos (0.011 g, 0.0295 mmol), sodiumt-butoxide (0.028 g, 0.295 mmol), morpholine (0.019 g, 0.222 mmol), 2 mLtoluene and 1 mL t-butanol. The sealed container was heated to 160° C.for 5 minutes in a microwave reactor. Workup entailed quenching intowater and extraction with ethyl acetate. The combined organic layer wasdried over MgSO₄, filtered and evaporated to afford a yellow oil.Purification on silica (EtOAc/hexane) afforded the product as an oil. ¹HNMR (400 MHz, CDCl₃) δ 1.12 (m, 2H) 1.39 (s, 9H) 1.48 (m, 2H) 1.62 (m,3H) 1.73 (m, 2H) 1.90 (m, 1H) 2.24 (m, 1H) 3.01 (s, 4H) 3.51 (s, 4H)3.54-3.58 (m, 4H) 3.65 (m, 1H) 3.80-3.87 (m, 4H) 6.73 (s, 1H) 7.50 (d,J=8.34 Hz, 2H) 7.73 (d, J=8.08 Hz, 3H) MS 685.3 [M+1]⁺.

H.3-Cyclopentyl-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(piperazine-1-sulfonyl)-phenyl]-propionamide

Title compound G,4-{4-[2-Cyclopentyl-1-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperazine-1-carboxylicacid tert-butyl ester (0.26 g, 0.378 mmol) was dissolved in 5 mL DCM and2 mL of TFA was added. The solution was stirred for 1 h and thenevaporated to afford a crude oil. The residue was partitioned between 2NNaOH and ethyl acetate and extracted numerous times with ethyl acetate,dried over MgSO4, filtered and concentrated to afford a green solid.This material was taken on crude to the next reaction. ¹H NMR (400 MHz,DMSO) δ 1.07-1.16 (M, 2H) 1.39-1.50 (m, 2H) 1.52-1.63 (m, 3H) 1.68-1.79(m, 3H) 2.16 (m, 1H) 2.71 (d, J=4.80 Hz, 4H) 2.76 (d, J=5.05 Hz, 4H)3.43-3.51 (m, 4H) 3.67-3.74 (m, 4H) 4.07 (d, J=8.84 Hz, 1H) 6.97 (d,J=9.09 Hz, 1H) 7.64-7.69 (m, 2H) 7.69-7.73 (m, 2H) 7.88 (d, J=9.09 Hz,1H) MS 585.31 [M+1]⁺.

I.(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide

Title compound H,3-Cyclopentyl-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(piperazine-1-sulfonyl)-phenyl]-propionamide(0.21 g, 0.354 mmol was suspended in formaldehyde (2 mL) to which 1 mLof formic acid was added. The mixture was heated to 70° C. for 7 hbefore being cooled and subsequently quenched into 2N NaOH and extractedwith ethyl acetate. The combined organic layer was dried over MgSO4,filtered and evaporated to provide a brown foam which was purified oversilica (0-20% EtOAc: methanol) to afford a white foam. This material waspurified on a Chiracel column to afford pure(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamideas a white solid. ¹H NMR (400 MHz, DMSO) δ 1.14 (m, 2H) 1.43 (d, J=4.80Hz, 2H) 1.57 (d, J=8.34 Hz, 3H) 1.72 (d, J=5.05 Hz, 2H) 1.75-1.83 (m,1H) 2.10 (s, 3H) 2.16 (m, 1H) 2.33 (d, J=4.04 Hz, 4H) 2.87 (s, 4H)3.41-3.49 (m, 4H) 3.67-3.74 (m, 4H) 4.07 (t, J=7.58 Hz, 1H) 6.97 (d,J=9.09 Hz, 1H) 7.64-7.69 (m, 2H) 7.69-7.75 (m, 2H) 7.87 (d, J=8.84 Hz,1H)

MS 599.2 [M+1]⁺.

EXAMPLE 31-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperidine-4-carboxylicacid

A. 3-Cyclopentyl-2-(4-nitro-phenyl)-propionic Acid Ethyl Ester

To a 1 L round bottom flask containing 250 mL of 9:1 THF/DMPU at −78 Care added under nitrogen 11 mL (78.6 mmol) anhydrous DIEA followed byrapid addition of 32 mL of 2.5 M n-BuLi in hexanes. After 10 min at −78°C. a solution of 15.4 g (74 mmol) of p-nitrophenylacetic acid, ethylester in 100 mL of 9:1 THF/DMPU is added dropwise over 30 min. A deeppurple solution results, and the reaction mixture is stirred at −78° C.for 30 min and then cyclopentyl methyl iodide (17.6 g, 78 mmol) in 50 mLof 9:1 THF/DMPU is added. The reaction is stirred while warming slowlyto RT overnight. The mixture is poured into 1 L of 1 N HCl and extractedtwice with MTBE. The combined MTBE extracts are washed with brine, driedover anhydrous magnesium sulfate, filtered and reduced to an orange oil.Flash chromatography over silica eluting with 4:1 hexane/MTBE affords3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester as an orangeoil: ¹H NMR (400 MHz, CDCl₃) δ 1.0-1.1 (m, 2H), 1.2 (t, 3H, J=7.2),1.4-1.8 (m, 5H), 1.8-1.9 (m, 2H), 2.1-2.25 (m, 2H), 3.74 (t, 1H, J=7.8),4.1 (m, 2H), 7.51 (d, 2H, J=8.8), 8.19 (d, 2H, J=8.8); LC/MS 290 (M−1).

B. 3-Cyclopentyl-2-(4-nitro-phenyl)-propionic Acid

The title A compound, 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acidethyl ester (3.6 g, 12.3 mmol) is dissolved in 25 mL of methanol andaqueous NaOH (0.70 g, 17.5 mmol in 4 mL of water) is added and themixture is stirred at RT overnight. The methanol is removed underreduced pressure and the residue is diluted with 100 mL of water andextracted with ether. The aqueous layer is then acidified with 1N HCland then extracted with ethyl acetate. The combined ethyl acetate layersare dried over anhydrous magnesium sulfate, filtered and reduced undervacuum to a crude orange oil. The crude oil is triturated with 100 mL ofhexane/10-15 mL of ether to produce3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid as a solid: ¹H NMR (400MHz, CDCl₃) δ1.0-1.1 (m, 2H), 1.4-1.8 (m, 5H), 1.8-1.9 (m, 2H), 2.1-2.25(m, 2H), 3.74 (t, 1H, J=7.8), 7.51 (d, 2H, J=8.8), 8.19 (d, 2H, J=8.8);LC/MS 218 (—CO₂, M−1), 279 (M+NH₄ ⁺).

C.3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-(4-nitro-phenyl)-propionamide

The title B compound, 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid(7.5 g, 28.5 mmol) is dissolved in 25 mL of thionyl chloride and a dropof DMF and the mixture stirred at RT for 5-6 h. The excess of thionylchloride is removed under reduced pressure. The residue is then taken upin DCM and added dropwise to a solution of the title E compound inExample 1,5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (5.2 g, 28.5 mmol)in 25 mL of pyridine. The reaction mixture is stirred for 5 h beforebeing evaporated to remove the pyridine. The residue is partitionedbetween ethyl acetate and brine, extracted with ethyl acetate. Thecombined organic layers are washed with saturated sodium bicarbonate,brine, dried over anhydrous magnesium sulfate, filtered and then reducedto an orange-brown solid. This is then vacuum dried to afford3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-(4-nitro-phenyl)-propionamideas a foam: ¹H NMR (400 MHz, CDCl₃) δ 1.0-1.1 (m, 2H), 1.4-1.8 (m, 5H),1.8-1.9 (m, 2H), 2.1-2.25 (m, 2H), 3.6 (t, 1H, J=7.8), 4.01 (s, 3H), 6.8(d, 1H, J=8.8), 7.4 (d, 2H, J=8.6), 7.8 (d, 1H, J=8.8 Hz), 8.19 (d, 2H,J=8.6 Hz), 9.3 (s, 1H); LC/MS 427 (M+1).

D.2-(4-Amino-phenyl)-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-propionamide

The title C compound,3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-(4-nitro-phenyl)-propionamide(12 g, 28.2 mmol) is diluted with 160 mL of ethanol and 150 mL aceticacid. 8 g of iron powder (325 mesh, 0.14 mol) is added and the mixtureheated to reflux. Once reflux begins the mixture is stirred vigorouslyand then heating is discontinued and the mixture is allowed to coolslowly. The solvents are removed and the residue is treated with 250 mLof water. Saturated sodium bicarbonate is added carefully to bring themixture to a pH of 8-9. The mixture is extracted with ethyl acetate,washed with brine, dried and evaporated to give an orange solid which istriturated from hexane. The resulting solid is collected by filtrationto afford2-(4-amino-phenyl)-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-propionamide:¹H NMR (400 MHz, CDCl₃) δ 1.0-1.1 (m, 2H), 1.4-1.8 (m, 5H), 1.8-1.9 (m,2H), 2.1-2.25 (m, 2H), 3.6 (t, 1H, J=7.8), 3.98 (s, 3H), 6.7 (d, 1H,J=8.8), 6.8 (d, 2H, J=8.6), 7.2 (d, 2H, J=8.6), 7.8 (d, 1H, J=8.8);LC/MS 397 (M+1).

E.4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonylChloride

The title D compound,2-(4-amino-phenyl)-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-propionamide(2.0 g, 5.1 mmol) is dissolved in 50 mL of acetic acid and 20 mL ofconcentrated HCl and the mixture is cooled to 0° C. A solution of 0.35 g(5.1 mmol) of NaNO₂ in 5 mL of water is added dropwise and the mixtureis stirred for 30 min. The resulting yellow solution is then added to180 mL of a solution prepared by bubbling 74 g of sulfur dioxide gasinto 740 mL of glacial acetic acid followed by addition of 30 g of CuCl₂in 35-40 mL water. The resulting mixture is filtered through filterpaper to obtain a clear green solution) and the mixture is stirred at RTovernight (the initial black-green solution transforms to a light greensolution after 24 h). The resulting mixture is poured onto 500 g of iceand the precipitated solids are collected by filtration, washed withwater and then dissolved in ethyl acetate, washed with brine, dried overanhydrous magnesium sulfate, filtered and evaporated to afford a yellowfoam. This material is flash chromatographed over silica eluting with7:3 hexane/ethyl acetate to afford4-[2-cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonylchloride as a stable yellow foam: ¹H NMR (400 MHz, CDCl₃) δ 1.0-1.1 (m,2H), 1.4-1.8 (m, 5H), 1.8-1.9 (m, 2H), 2.1-2.25 (m, 2H), 3.7 (t, 1H,J=7.8), 4.01 (s, 3H), 6.8 (d, 1H, J=8.8), 7.5 (d, 2H, J=8.6), 7.8 (d,1H, J=8.8), 8.19 (d, 2H, J=8.6), 9.3 (s, 1H); LC/MS 480 (M+1).

F.1-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperidine-4-carboxylicAcid Ethyl Ester

Title compound E,4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonylchloride (120 mg, 0.2499 mmol) was dissolved in dichloromethane. To thiswas added a solution of piperidine-4-carboxylic acid ethyl ester (38 μL,0.2499 mmol) and diisopropylethylamine (87 μL, 0.4998 mmol) indichloromethane. The reaction was stirred at room temperature for 1hour, then concentrated. The residue was partitioned between 1Nhydrochloric acid and ethyl acetate. The organic layer was separated,dried over anhydrous magnesium sulfate, filtered, and concentrated toafford a yellow oil. The crude was then purified via columnchromatography 10-90% ethyl acetate in hexanes to afford the desiredproduct as a yellow foam (107 mg, 71%). ¹H NMR (400 MHz, CHLOROFORM-d) δppm 1.20 (t, J=7.07 Hz, 3 H) 1.10-1.22 (m, 2 H) 1.50 (d, J=2.78 Hz, 2 H)1.49 (br. s., 1 H) 1.63 (dd, J=14.91, 7.83 Hz, 2 H) 1.62 (br. s., 1 H)1.81 (dd, J=13.64, 3.79 Hz, 3 H) 1.95 (t, J=7.07 Hz, 2 H) 1.91 (d,J=7.83 Hz, 1 H) 2.21-2.31 (m, 2 H) 2.53 (td, J=11.43, 2.91 Hz, 2 H)3.61-3.71 (m, 3 H) 4.00 (s, 3 H) 4.09 (q, J=7.07 Hz, 2 H) 6.80 (d,J=8.84 Hz, 1 H) 7.52 (d, J=8.59 Hz, 2 H) 7.74-7.84 (m, 3 H) LC/MS 601.3(M+1) 599.4 (M−1)

G.1-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperidine-4-carboxylicAcid

Sodium hydroxide (12 mg, 0.2996 mmol) was dissolved in a minimum amountof water and added to a solution of title compound F,1-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperidine-4-carboxylicacid ethyl ester (90 mg, 0.1498 mmol) in methanol. The reaction wasstirred at room temperature overnight, poured into 1N hydrochloric acid,and extracted with ethyl acetate. Extracts were combined, dried overanhydrous magnesium sulfate, filtered, and concentrated to afford thetitle compound as a yellow foam (63 mg, 73%). 1H NMR (400 MHz, DMSO-D₆)δ ppm 1.05-1.16 (m, 2 H) 1.36-1.47 (m, 2 H) 1.49-1.61 (m, 5 H) 1.66-1.72(m, 3 H) 1.75 (s, 1 H) 1.78-1.80 (m, 1 H) 1.92-2.02 (m, 1 H) 2.08-2.18(m, 1 H) 2.40 (t, J=9.85 Hz, 2 H) 3.35 (d, J=11.37 Hz, 2 H) 3.82-3.92(m, 4 H) 6.74 (d, J=8.59 Hz, 1 H) 7.59-7.67 (m, 4 H) 7.79 (d, J=8.84 Hz,1 H) LC/MS 573.1 (M+1) 571.4 (M−1) EC₅₀ in primary enzyme assay 7.1 μM

EXAMPLE 4

The following examples may be prepared by a skilled artisan using themethods described herein above.

4-13-Cyclopentyl-N-isoquinolin-1-yl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 507, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14-1.25 (m, 2 H) 1.41-1.51(m, 2 H) 1.53-1.62 (m, 2 H) 1.67-1.78 (m, 2 H) 1.79-1.90 (m, 2 H)2.18-2.27 (m, 1 H) 2.65-2.76 (m, 5 H) 2.88 (s, 1 H) 3.10 (br. s., 1 H)3.41 (d, J=11.87 Hz, 2 H) 3.76 (d, J=12.38 Hz, 2 H) 4.96 (br. s., 1 H)7.76-7.82 (m, 2 H) 7.86-7.91 (m, 2 H) 7.92-7.98 (m, 2 H) 8.06 (t, J=7.58Hz, 1 H) 8.16 (d, J=8.08 Hz, 1 H) 8.22 (d, J=6.57 Hz, 1 H) 9.00 (br. s.,1 H) 11.15 (br. s., 1 H). EC₅₀ in primary enzyme assay 1.1 μM

4-23-Cyclopentyl-N-(1-methyl-1H-benzoimidazol-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 510, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (t, J=7.07 Hz, 2 H)1.42 (br. s., 2 H) 1.56 (br. s., 2 H) 1.76 (dd, J=13.26, 7.20 Hz, 3 H)2.06-2.17 (m, 4 H) 2.32 (br. s., 4 H) 2.85 (br. s., 4 H) 3.29 (s, 3 H)3.42 (br. s., 1 H) 3.54 (br. s., 2H) 7.14-7.23 (m, 2 H) 7.42 (br. s., 2H) 7.67 (t, J=7.96 Hz, 4 H).

4-33-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-[1,3,4]thiadiazol-2-yl-propionamide:MS M+1 464, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.08-1.19 (m, 2 H) 1.38-1.48(m, 2 H) 1.51-1.61 (m, 3 H) 1.64-1.75 (m, 2 H) 2.08-2.19 (m, 1 H) 2.11(s, 3 H) 2.33 (s, 4 H) 2.87 (s, 4 H) 4.10 (t, J=7.8 Hz, 1 H) 7.65 (d,J=8.4 Hz, 2 H) 7.72 (d, J=8.4 Hz, 2H) 9.17 (s, 1 H).

4-43-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-quinolin-2-yl-propionamide:MS M+1 507, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.22 (m, 2 H) 1.15 (dd,J=11.62, 6.06 Hz, 1 H) 1.44 (dd, J=7.20, 4.42 Hz, 1 H) 1.56 (dd, J=1.62,3.28 Hz, 1 H) 1.52-1.59 (m, 1 H) 1.73 (dt, J=13.14, 6.57 Hz, 2 H) 2.18(ddd, J=12.95, 8.53, 6.57 Hz, 1 H) 2.56-2.67 (m, 2 H) 2.70 (d, J=3.79Hz, 3 H) 3.13 (br. s., 2 H) 3.41 (d, J=11.62 Hz, 2 H) 3.74 (d, J=12.13Hz, 2 H) 4.13 (d, J=3.28 Hz, 1 H) 7.49 (dd, J=15.03, 1.14 Hz, 1 H)7.69-7.80 (m, 2 H) 7.76 (d, J=2.02 Hz, 3 H) 7.90 (d, J=7.58 Hz, 1 H)8.23-8.30 (m, 1 H) 8.32-8.37 (m, 1 H) 10.35 (br. s., 1 H) 11.23 (s, 1H).

4-5N-(6-Chloro-pyridazin-3-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 493, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (d, J=6.32 Hz, 1 H)1.27 (br. s., 1 H) 1.40-1.52 (m, 1 H) 1.43 (d, J=4.55 Hz, 1 H) 1.56 (br.s., 2 H) 1.62 (d, J=7.58 Hz, 1 H) 1.73 (dd, J=13.14, 6.82 Hz, 3 H) 2.13(dd, J=6.69, 1.89 Hz, 1 H) 2.53 (br. s., 2 H) 2.66-2.77 (m, 3 H) 3.12(br. s., 2 H) 3.42 (br. S., 2 H) 3.73 (br. s., 2 H) 4.18 (t, J=7.45 Hz,1 H) 4.13 (dd, J=5.56, 3.28 Hz, 1 H) 7.67-7.78 (m, 4 H) 7.85 (d, J=9.60Hz, 1 H) 8.37 (d, J=9.35 Hz, 1 H) 9.87 (br. s., 1 H) 11.68 (s, 1 H).

4-63-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-methyl-thiazol-2-yl)-propionamide:MS M+1 477, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=10.99 Hz, 2 H)1.12 (br. s., 1 H) 1.44 (dd, J=7.33, 4.55 Hz, 2 H) 1.57 (dq, J=14.75,7.46 Hz, 2 H) 1.52-1.62 (m, 2 H) 1.66-1.77 (m, 1 H) 1.73 (dd, J=13.26,6.44 Hz, 2 H) 2.15 (ddd, J=13.39, 8.46, 7.20 Hz, 1 H) 2.32 (d, J=1.26Hz, 3 H) 2.77 (s, 3 H) 3.15 (br. s., 2 H) 3.43 (br. s., 2 H) 3.75 (br.s., 2 H) 4.05 (dd, J=8.46, 6.69 Hz, 1 H) 7.13 (d, J=1.26 Hz, 1 H)7.66-7.72 (m, 2 H) 7.74-7.79 (m, 2 H) 12.26 (s, 1 H);

4-72-{3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazole-4-carboxylicacid: MS M+1 507, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.02-1.13 (m, 2 H)1.34-1.44 (m, 2 H) 1.50-1.58 (m, 2 H) 1.58-1.63 (m, 1 H) 1.64-1.69 (m, 2H) 2.00-2.09 (m, 1 H) 2.10 (s, 2 H) 2.33 (d, J=4.29 Hz, 4 H) 2.85 (s, 4H) 3.57 (t, J=7.45 Hz, 1H) 6.73 (s, 1 H) 7.57 (d, J=8.4 Hz, 2 H) 7.63(d, J=8.4 Hz, 2 H).

4-82-[3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-propionylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester: MS M+1 591, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm1.15 (t, J=7.07 Hz, 7 H) 1.07-1.17 (m, 1 H) 1.47 (s, 8 H) 1.57-1.65 (m,6 H) 1.67-1.77 (m, 2 H) 1.88 (t, J=14.02 Hz, 1 H) 2.22 (dt, J=13.64,7.45 Hz, 1 H) 2.69 (br. s., 2 H) 3.24 (q, J=7.16 Hz, 4 H) 3.63 (t,J=7.58 Hz, 1 H) 3.67-3.75 (m, 2 H) 4.54 (s, 2 H) 7.44 (d, J=8.59 Hz, 2H) 7.78 (d, J=8.34 Hz, 2 H) 8.72 (br. s., 1 H). EC₅₀ in primary enzymeassay 0.095 μM

4-93-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-propionamide:MS M+1 491, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.07 Hz, 6 H)1.12 (d, J=19.96 Hz, 1 H) 1.11 (d, J=8.34 Hz, 1 H) 1.43 (dd, J=7.20,4.67 Hz, 2 H) 1.51-1.60 (m, 1 H) 1.56 (t, J=7.58 Hz, 2 H) 1.73 (dt,J=13.20, 6.66 Hz, 2 H) 1.65 (d, J=1.01 Hz, 1 H) 2.12 (dd, J=6.95, 4.67Hz, 1 H) 2.85 (br. s., 2 H) 3.14 (q, J=7.07 Hz, 4 H) 3.40 (br. s., 2 H)4.03 (dd, J=8.59, 6.57 Hz, 1 H) 4.27 (br. s., 2 H) 7.58 (d, J=8.34 Hz, 2H) 7.77 (d, J=8.34 Hz, 2 H) 9.39 (br. s., 1 H) 12.52 (s, 1 H).

4-103-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-propionamide:MS M+1 505, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.07 Hz, 6 H)1.14 (br. s., 1 H) 1.11 (d, J=11.62 Hz, 2 H) 1.42 (d, J=5.05 Hz, 2 H)1.51-1.62 (m, 3 H) 1.73 (dd, J=13.52, 6.69 Hz, 3 H) 2.12 (dt, J=8.34,6.82 Hz, 1 H) 2.91 (br. s., 4 H) 3.14 (q, J=7.07 Hz, 4 H) 3.64 (br. s.,1 H) 4.02 (dd, J=8.46, 6.44 Hz, 1 H) 4.26 (br. s., 1 H) 4.51 (br. s., 1H) 7.58 (d, J=8.34 Hz, 2 H) 7.77 (d, J=8.34 Hz, 2 H) 10.59 (br. s., 1 H)12.55 (s, 1 H).

4-113-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-pyrazin-2-yl-propionamide:MS M+1 431, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.13 (q, J=7.24 Hz, 6H) 1.45-1.54 (m, 2 H) 1.49 (dd, J=7.58, 4.80 Hz, 2 H) 1.63 (td, J=7.52,3.41 Hz, 2 H) 1.70 (d, J=7.33 Hz, 1 H) 1.89 (dd, J=13.64, 7.33 Hz, 1 H)2.22 (t, J=6.82 Hz, 1 H) 3.24 (q, J=7.07 Hz, 4 H) 3.67 (t, J=7.58 Hz, 1H) 7.51 (d, J=8.34 Hz, 2 H) 7.79 (d, J=8.59 Hz, 2 H) 8.10 (s, 1 H) 8.18(d, J=1.77 Hz, 1 H) 8.34 (d, J=2.53 Hz, 1 H) 9.54 (s, 1 H).

4-123-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-pyridin-2-yl-propionamide:MS M+1 430, 1H NMR (400 MHz, DMSO-d6) δppm 1.01 (t, J=7.20 Hz, 6 H)1.07-1.17 (m, 2 H) 1.42 (dd, J=7.33, 4.55 Hz, 2 H) 1.52-1.61 (m, 3 H)1.67 (ddd, J=13.26, 6.82, 6.69 Hz, 3 H) 2.11 (ddd, J=12.95, 8.78, 6.32Hz, 1 H) 3.12 (q, J=7.07 Hz, 4 H) 4.07 (dd, J=8.46, 6.44 Hz, 1 H) 7.08(ddd, J=6.69, 5.43, 1.01 Hz, 1 H) 7.61 (d, J=8.34 Hz, 2 H) 7.71-7.77 (m,1 H) 7.74 (d, J=8.59 Hz, 2 H) 8.05 (d, J=8.34 Hz, 1 H) 8.28 (dd, J=4.80,1.01 Hz, 1 H) 10.78 (s, 1 H).

4-133-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide:MS M+1 498, 1H NMR (400 MHz, DMSO-d6) δppm 1.02 (q, J=7.07 Hz, 6 H)1.06-1.16 (m, J=11.40, 7.63, 7.63, 3.41 Hz, 2 H) 1.42 (dd, J=7.20, 4.67Hz, 2 H) 1.51-1.62 (m, 1 H) 1.55 (td, J=8.97, 7.07 Hz, 2 H) 1.69 (ddd,J=13.14, 6.95, 6.69 Hz, 3 H) 2.12 (ddd, J=13.20, 8.27, 6.82 Hz, 1 H)3.12 (q, J=7.07 Hz, 4 H) 4.13 (dd, J=8.21, 6.69 Hz, 1 H) 7.61 (d, J=8.34Hz, 2 H) 7.57 (d, J=7.33 Hz, 1 H) 7.75 (d, J=8.59 Hz, 2 H) 8.04 (t,J=7.96 Hz, 1 H) 8.35 (d, J=8.59 Hz, 1 H) 11.21 (s, 1 H).

4-143-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-pyrimidin-2-yl-propionamide:MS M+1 431, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.12-1.17 (m, 8 H) 1.48(d, J=7.33 Hz, 3 H) 1.72 (d, J=11.62 Hz, 2 H) 1.68 (br. s., 1 H) 1.85(dd, J=13.52, 7.20 Hz, 2 H) 2.26 (t, J=14.02 Hz, 1 H) 2.26 (d, J=13.39Hz, 1 H) 3.22 (d, J=7.07 Hz, 4 H) 3.20 (s, 1 H) 7.01 (t, J=4.80 Hz, 1 H)7.55 (d, J=8.34 Hz, 2 H) 7.75 (d, J=8.34 Hz, 2 H) 8.58 (d, J=4.80 Hz, 2H).

4-153-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-thiazol-2-yl-propionamide:MS M+1 436, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (t, J=7.07 Hz, 5 H)1.10 (ddd, J=119.77, 8.15, 3.66 Hz, 1 H) 1.42 (td, J=7.52, 3.16 Hz, 2 H)1.49-1.60 (m, 1 H) 1.55 (d, J=5.05 Hz, 2 H) 1.65-1.76 (m, 1 H) 1.71 (dd,J=13.26, 6.69 Hz, 2 H) 2.13 (ddd, J=13.33, 8.53, 6.95 Hz, 1 H) 3.12 (q,J=7.16 Hz, 4 H) 3.31 (s, 2 H) 4.02 (dd, J=8.46, 6.69 Hz, 1 H) 7.20 (d,J=3.54 Hz, 1 H) 7.45 (d, J=3.54 Hz, 1 H) 7.58 (d, J=8.34 Hz, 2 H) 7.75(d, J=8.34 Hz, 2 H) 12.41 (s, 1 H). EC₅₀ in primary enzyme assay 0.06 μM

4-166-[3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-propionylamino]-nicotinicacid: MS M+474, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01 (t, J=7.07 Hz, 6 H)1.13 (m, 2 H) 1.42 (br. s., 2 H) 1.55 (br. s., 3 H) 1.65 (d, J=19.20 Hz,3 H) 2.11 (br. s., 1 H) 3.11 (q, J=6.82 Hz, 4 H) 4.05 (br. s., 1 H)7.59-7.64 (m, 2 H) 7.73 (d, J=8.34 Hz, 2 H) 7.90 (d, J=9.09 Hz, 1 H)8.02 (d, J=8.34 Hz, 1 H) 8.63 (s, 1 H) 10.73 (s, 1 H).

4-173-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(1H-tetrazol-5-yl)-propionamide:MS M+1 448.

4-18N-(5-Chloro-thiazol-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 497, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.19 (m, 2 H) 1.42 (br.s., 1 H) 1.44 (dd, J=7.20, 4.67 Hz, 1 H) 1.51-1.61 (m, 3 H) 1.68 (br.s., 1 H) 1.73 (d, J=12.13 Hz, 1 H) 1.75-1.81 (m, 1 H) 2.09-2.19 (m, 1 H)2.76 (s, 3 H) 3.15 (br. s., 2 H) 3.43 (br. s., 2 H) 3.75 (br. s., 2 H)4.07 (t, J=7.45 Hz, 1 H) 7.52 (s, 1 H) 7.69 (d, J=8.34 Hz, 2 H)7.75-7.79 (m, 2 H) 12.73 (s, 1 H).

4-193-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(4-methyl-thiazol-2-yl)-propionamide:MS M+1 477, 1H NMR (400 MHz, DMSO-d6) δ ppm-1.13 (d, J=3.03 Hz, 2H) 1.44(dd, J=7.20, 4.67 Hz, 2 H) 1.52-1.61 (m, 3 H) 1.66-1.77 (m, 3 H) 2.16(ddd, J=13.26, 8.72, 7.07 Hz, 1 H) 2.24 (d, J=1.01 Hz, 3 H) 2.29-2.37(m, 1 H) 2.77 (s, 3 H) 3.15 (br. s., 2 H) 3.44 (br. s., 1 H) 3.49 (br.s., 1 H) 3.74 (br. s., 2 H) 4.04 (dd, J=8.59, 6.57 Hz, 1H) 6.75 (d,J=1.01 Hz, 1 H) 7.63-7.72 (m, 2 H) 7.74-7.79 (m, 2 H) 9.34 (br. s., 1 H)12.39 (br. s., 1 H).

4-203-Cyclopentyl-N-(1H-indazol-3-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 496, 1H NMR (400 MHz, DMSO-d6) δ ppm-1.11-1.22 (m, 2 H) 1.42 (dd,J=7.33, 3.79 Hz, 2 H) 1.52-1.59 (m, 3 H) 1.63-1.72 (m, 4 H) 1.84 (dt,J=13.39, 6.69 Hz, 1 H) 2.21-2.30 (m, 1 H) 2.74 (s, 3 H) 3.13 (br. s., 2H) 3.52 (br. s., 8 H) 3.74 (br. s., 2 H) 5.16 (dd, J=8.34, 6.82 Hz, 1 H)6.58 (br. s., 1 H) 7.35 (t, J=7.58 Hz, 1 H) 7.53-7.58 (m, 1 H) 7.72-7.78(m, 4 H) 7.89 (d, J=7.83 Hz, 1 H) 8.26 (d, J=8.34 Hz, 1 H) 9.28 (br. s.,1 H).

4-213-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-propionamide:MS M+1 533, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.08-1.19 (m, 2 H) 1.43 (dd,J=7.20, 4.67 Hz, 2 H) 1.51-1.62 (m, 3 H) 1.64-1.74 (m, 2 H) 1.81-1.87(m, 2 H) 2.11-2.21 (m, 4 H) 2.40 (s, 4 H) 2.73 (s, 3 H) 2.89 (s, 4 H)7.64 (d, J=8.3 Hz, 2 H) 7.73 (d, J=8.3 Hz, 2 H) 7.95 (s, 1 H).

4-22N-(5-Bromo-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1594, 1H NMR (400 MHz, DMSO-D6) □ ppm 1.07-1.19 (m, 2 H) 1.39-1.49(m, 2 H) 1.52-1.63 (m, 3 H) 1.66-1.76 (m, 2 H) 1.79-1.86 (m, 1 H)2.09-2.19 (m, 4 H) 2.33 (s, 4 H) 2.87 (s, 4 H) 7.65-7.70 (m, 3 H)7.71-7.75 (m, 2 H) 8.06 (d, J=8.5 Hz, 1 H). EC₅₀ in primary enzyme assay0.39 μM

4-236-{3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-nicotinicacid: MS M+1 501, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.18 (m, 2 H)1.43 (dd, J=7.20, 4.67 Hz, 2 H) 1.51-1.62 (m, 3 H) 1.64-1.74 (m, 3 H)2.06-2.16 (m, 4 H) 2.31 (t, J=4.55 Hz, 5 H) 2.85 (br. s., 4 H) 4.08 (d,J=7.33 Hz, 1 H) 7.64-7.71 (m, 4 H) 7.91 (d, J=8.59 Hz, 1 H) 8.03 (dd,J=8.46, 2.15 Hz, 1 H) 8.64 (d, J=1.26 Hz, 1 H) 10.76 (s, 1 H). EC₅₀ inprimary enzyme assay 1.4 μM

4-24(2-{3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazol-4-yl)-aceticacid ethyl ester: MS M+1 549, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.04-1.15(m, 5 H) 1.40 (dd, J=7.07, 4.55 Hz, 2 H) 1.47-1.57 (m, 3 H) 1.62-1.73(m, 3 H) 2.05-2.15 (m, 4 H) 2.28 (t, J=4.55 Hz, 4 H) 2.83 (br. s., 4 H)3.26 (s, 9 H) 3.26 (s, 6 H) 3.62 (s, 2H) 3.95-4.05 (m, 1 H) 6.94 (s, 1H) 7.56-7.61 (m, 2 H) 7.65-7.69 (m, 2 H) 12.46 (s, 1 H).

4-25N-Benzothiazol-2-yl-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 513, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.19-1.30 (m, 2 H) 1.54 (dd,J=6.95, 4.42 Hz, 2 H) 1.62-1.74 (m, 3 H) 1.85 (br. s., 2 H) 1.90 (ddd,J=13.52, 6.95, 6.82 Hz, 1 H) 2.23-2.34 (m, 1 H) 2.82-2.88 (m, 3 H) 3.24(br. s., 2 H) 3.52 (br. s., 2 H) 3.84 (br. s., 2 H) 4.19-4.27 (m, 1 H)7.38-7.43 (m, 1 H) 7.50-7.56 (m, 1 H) 7.80-7.85 (m, 3 H) 7.86-7.90 (m, 2H) 8.06 (d, J=7.33 Hz, 1 H) 9.36 (br. s., 1 H) 12.82 (s, 1 H).

4-26N-(6-Bromo-benzothiazol-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 593, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.13 (m, 2H) 1.30-1.41(m, 2 H) 1.44-1.55 (m, 3 H) 1.57-1.64 (m, 2 H) 1.72 (ddd, J=13.58, 7.07,6.88 Hz, 1 H) 2.09 (dt, J=13.20, 7.80 Hz, 1 H) 2.67 (s, 3 H) 3.06 (br.s., 2 H) 3.34 (br. s., 2 H) 3.67 (br. s., 2 H) 4.05 (t, J=7.58 Hz, 1 H)7.49 (dd, J=8.59, 2.02 Hz, 1 H) 7.57-7.60 (m, 1-H) 7.61-7.66 (m, 2 H)7.68-7.72 (m, 2 H) 8.16 (d, J=2.02 Hz, 1 H) 9.28 (br. s., 1 H) 12.75 (s,1 H).

4-273-Cyclopentyl-N-(6-methanesulfonyl-benzothiazol-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 591, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (br. s., 2 H) 1.46 (d,J=7.83 Hz, 27H) 1.60 (br. s., 3 H) 1.77 (s, 2 H) 1.80-1.90 (m, 1 H) 2.21(d, J=12.88 Hz, 1 H) 2.77 (br. s., 3 H) 3.26 (s, 3 H) 3.45 (br. s., 2 H)3.77 (br. s., 3 H) 4.18 (t, J=7.58 Hz, 1 H) 7.72-7.78 (m, 2 H) 7.78-7.83(m, 2 H) 7.93-7.99 (m, 2 H) 8.65 (s, 1 H) 9.32 (br. s., 1 H) 13.06 (s, 1H).

4-283-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-phenoxy-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 606, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.18 (m, 2 H) 1.43 (dd,J=7.07, 4.55 Hz, 2 H) 1.51-1.62 (m, 3 H) 1.70 (br. s., 1 H) 1.77 (td,J=13.26, 6.32 Hz, 1 H) 2.09-2.20 (m, 1 H) 2.57 (br. s., 2 H) 2.72 (br.s., 3 H) 3.11 (br. s., 2H) 3.42 (br. s., 2 H) 3.73 (br. s., 2 H) 4.14(t, J=7.45 Hz, 1 H) 7.08-7.17 (m, 3 H) 7.22 (t, J=7.45 Hz, 1 H)7.39-7.46 (m, 2 H) 7.68-7.79 (m, 4 H) 8.16 (d, J=8.84 Hz, 1 H) 10.01(br. s., 1 H) 12.81 (s, 1 H).

4-29(2-{3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazol-4-yl)-aceticacid: MS M+1 521, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (br. s., 2H)1.33-1.42 (m, 2 H) 1.47-1.56 (m, 3 H) 1.64-1.75 (m, 3 H) 2.03-2.13 (m, 4H) 2.26-2.36 (m, 4 H) 2.85 (br. s., 4 H) 3.22 (br. s., 2 H) 4.52 (br.s., 1 H) 6.60 (br. s., 1 H) 7.64 (d, J=8.34 Hz, 2 H) 7.67-7.77 (m, 2 H).

4-302-{3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-benzothiazole-6-carboxylicacid ethyl ester: MS M+1 585, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm1.09-1.20 (m, 2 H) 1.42 (t, J=7.07 Hz, 3 H) 1.46-1.56 (m, 2 H) 1.58-1.69(m, 4 H) 1.69-1.81 (m, 8 H) 1.87-1.98 (m, 1 H) 2.23-2.30 (m, 4 H) 2.48(t, J=4.80 Hz, 4 H) 3.05 (br. s., 4 H) 3.74 (t, J=7.58 Hz, 1 H) 4.41 (q,J=7.24 Hz, 2 H) 7.46-7.53 (m, 2 H) 7.68-7.76 (m, 3 H) 8.12 (dd, J=8.59,1.77 Hz, 1 H) 8.54 (d, J=1.26 Hz, 1 H) 9.23 (br. s., 1 H).

4-312-{3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-benzothiazole-6-carboxylicacid: MS M+1 557, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.18 (m, 1 H)1.42 (dd, J=7.20, 4.93 Hz, 2 H) 1.54 (d, J=7.33 Hz, 1 H) 1.60 (d, J=7.07Hz, 2H) 1.70 (d, J=3.03 Hz, 1 H) 1.72 (d, J=6.82 Hz, 2 H) 2.10 (s, 4 H)2.32 (t, J=4.29 Hz, 4 H) 2.86 (br. s., 4 H) 3.79 (br. s., 1 H) 7.31 (br.s., 1 H) 7.64 (s, 4 H) 7.75 (br. s., 1 H) 8.13 (br. s., 3 H).

4-322-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-benzothiazole-6-carboxylicacid: MS M+1 558, 1H NMR (400 MHz, DMSO-D6) δppm 1.06-1.17 (m, 2 H)1.36-1.47 (m, 2 H) 1.51-1.62 (m, 3 H) 1.66-1.74 (m, 3 H) 2.07-2.17 (m,4H) 2.26-2.36 (m, 4 H) 2.86 (s, 4 H) 7.27 (d, J=8.1 Hz, 1 H) 7.60-7.67(m, 4 H) 7.74 (d, J=8.08 Hz, 1 H).

4-332-{3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-3-trifluoromethyl-phenyl]-propionylamino}-benzothiazole-6-carboxylicacid::MS M+1 625, 1H NMR (400 MHz, DMSO-d6) δppm 1.16 (d, J=8.08 Hz, 2H) 1.45 (br. s., 1 H) 1.44 (d, J=5.05 Hz, 1 H) 1.52-1.63 (m, 1 H) 1.58(d, J=8.59 Hz, 2 H) 1.74 (d, J=12.63 Hz, 2 H) 1.74 (br. s., 1 H) 1.85(ddd, J=13.52, 6.95, 6.82 Hz, 1 H) 2.23 (dd, J=15.54, 13.52 Hz, 1 H)2.80 (br. s., 3 H) 3.05 (br. s., 3 H) 3.31 (br. s., 2 H) 3.84 (br. s., 2H) 4.23 (t, J=7.45 Hz, 1 H) 7.80 (d, J=8.59 Hz, 1 H) 7.96 (dd, J=8.34,1.52 Hz, 1 H) 8.00 (dd, J=8.59, 1.77 Hz, 1 H) 8.08 (d, J=1.52 Hz, 1 H)8.12 (d, J=8.34 Hz, 1 H) 8.61 (d, J=1.52 Hz, 1 H) 12.95 (s, 1 H).

4-342-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-benzothiazole-6-carboxylicacid (2-methoxy-ethyl)-amide: MS M+1 614, 1H NMR (400 MHz, DMSO-d₆) δppm 1.16 (d, J=12.13 Hz, 2 H) 1.45 (br. s., 2 H) 1.62 (d, J=7.83 Hz, 2H) 1.57 (br. s., 14H) 1.73 (d, J=1.26 Hz, 2 H) 1.83 (br. s., 1 H) 2.17(br. s., 1 H) 2.69-2.78 (m, 4 H) 3.14 (br. s., 2 H) 3.27 (s, 3 H) 3.74(br. s., 2 H) 4.18 (t, J=7.20 Hz, 1 H) 7.70-7.81 (m, 5 H) 7.93 (d,J=8.59 Hz, 1 H) 8.47 (s, 1 H) 8.56 (br. s., 1 H) 10.32 (br. s., 1 H)12.93 (s, 1 H).

4-353-[(2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-benzothiazole-6-carbonyl)-amino]-propionicacid: MS M+1 629, 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (br. s., 2 H)1.45 (br. s., 2 H) 1.57 (br. s., 3 H) 1.73 (br. s., 2 H) 2.17 (br. s.,1H) 2.62 (br. s., 2 H) 2.72 (br. s., 4 H) 3.14 (br. s., 2 H) 3.27 (s, 3H) 3.45 (dd, J=10.23, 4.67 Hz, 6 H) 3.54 (br. s., 4 H) 3.74 (br. s., 2H) 4.18 (s, 1 H) 7.71-7.82 (m, 5 H) 7.92 (s, 1 H) 8.47 (s, 1 H) 8.57(br. s., 1 H) 10.33 (br. s., 1 H) 12.93 (s, 2 H).

4-363-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide:MS M+1 598, 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (br. s., 1 H) 1.10 (d,J=6.82 Hz, 1 H) 1.45 (br. s., 2 H) 1.57 (br. s., 2 H) 1.62 (br. s., 2 H)1.72 (br. s., 1 H) 1.81 (br. s., 2 H) 2.19 (d, J=5.31 Hz, 1 H) 2.72 (br.s., 4 H) 3.14 (br. s., 2 H) 3.37-3.49 (m, 2 H) 3.78 (br. s., 26H) 4.19(t, J=7.07 Hz, 1 H) 7.43 (d, J=8.34 Hz, 1 H) 7.71-7.76 (m, 2 H)7.77-7.85 (m, 1 H) 7.79 (d, J=8.34 Hz, 1 H) 8.12 (br. s., 1 H) 10.61(br. s., 1H) 12.92 (br. s., 1 H).

4-37N-(5-Chloro-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1548, 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-0.89 (m, 1 H) 1.14 (t,J=7.20 Hz, 2 H) 1.43 (br. s., 2 H) 1.56 (br. s., 3 H) 1.70 (br. s., 2 H)1.75-1.85 (m, 1 H) 2.57 (br. s., 2 H) 2.73 (br. s., 3 H) 3.13 (br. s., 2H) 3.40 (br. s., 6 H) 3.71-3.82 (m, 2 H) 4.12-4.19 (m, 1 H) 7.58 (d, 1H) 7.55 (s, 1 H) 7.69-7.80 (m, 3 H) 8.16 (d, J=8.59 Hz, 1 H) 9.85 (br.s., 1 H) 13.03 (s, 1 H).

4-38(2-{3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazolo[5,4-b]pyridin-5-yloxy)-aceticacid: MS M+1 588, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (br. s., 2 H)1.40 (d, J=6.32 Hz, 2 H) 1.53 (d, J=6.57 Hz, 3 H) 1.63-1.72 (m, 3 H)2.04-2.13 (m, 5 H) 2.32 (d, J=4.04 Hz, 5 H) 2.86 (br. s., 4 H) 3.58-3.64(m, 1 H) 4.25 (s, 2H) 6.47 (d, J=8.59 Hz, 1 H) 7.45 (d, J=8.59 Hz, 1 H)7.57-7.65 (m, 4 H).

4-393-Cyclopentyl-N-(5-fluoro-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 532, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=7.07 Hz, 2 H)1.43 (d, J=7.07 Hz, 2 H) 1.56 (d, J=4.29 Hz, 3 H) 1.72 (br. s., 2 H)1.75-1.86 (m, 1 H) 2.18 (br. s., 1 H) 2.60 (br. s., 2 H) 2.71 (br. s., 2H) 3.12 (br. s., 2 H) 3.32 (br. s., 4 H) 3.41 (br. s., 1 H) 3.75 (br.s., 1 H) 4.17 (br. s., 1 H) 7.27 (d, J=8.59 Hz, 1 H) 7.69-7.81 (m, 4 H)8.26-8.35 (m, 1 H) 10.22 (br. s., 1 H) 12.97 (s, 1 H).

4-403-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-vinyl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 540, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.25 (d, J=7.07 Hz, 3 H)1.55 (d, J=7.07 Hz, 3 H) 1.67 (d, J=7.07 Hz, 4 H) 1.82 (d, J=10.61 Hz, 2H) 1.94 (d, J=6.57 Hz, 1 H) 2.27 (s, 1 H) 2.67 (br. s., 2 H) 2.84 (d,J=3.79 Hz, 4 H) 3.22 (br. s., 2 H) 3.53 (br. s., 2 H) 3.85 (br. s., 2 H)4.28 (t, J=7.71 Hz, 1 H)-5.60 (dd, J=10.86, 1.26 Hz, 1H) 6.35 (dd,J=17.43, 1.26 Hz, 1 H) 7.00 (dd, J=17.56, 10.74 Hz, 1 H) 7.74 (d, J=8.34Hz, 1H) 7.82-7.86 (m, 2 H) 7.87-7.93 (m, 2 H) 8.17 (d, J=8.34 Hz, 1 H)10.08 (br. s., 1 H) 13.01 (s, 1 H).

4-413-Cyclopentyl-N-(5-ethyl-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 542, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.10-1.21 (m, 2 H) 1.26 (t,J=7.58 Hz, 3 H) 1.45 (dd, J=7.20, 4.67 Hz, 2 H) 1.52-1.64 (m, 3 H) 1.73(s, 2 H) 1.82 (ddd, J=13.58, 7.07, 6.88 Hz, 1 H) 2.13-2.22 (m, 1 H) 2.67(s, 2 H) 2.72 (d, J=4.04 Hz, 3 H) 2.85 (q, J=7.66 Hz, 2 H) 3.14 (s, 2 H)3.43 (d, J=12.38 Hz, 2 H) 3.74 (s, 2 H) 4.18 (t, J=7.58 Hz, 1 H) 7.37(d, J=8.34 Hz, 1 H) 7.70-7.76 (m, 2 H) 7.76-7.81 (m, 2H) 8.01 (d, J=8.34Hz, 1H).

4-423-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 599, 1H NMR (400 MHz, DMSO) δ 1.14 (m, 2H) 1.43 (d, J=4.80 Hz,2H) 1.57 (d, J=8.34 Hz, 3H) 1.72 (d, J=5.05 Hz, 2H) 1.75-1.83 (m, 1H)2.10 (s, 3H) 2.16 (m, 1H) 2.33 (d, J=4.04 Hz, 4H) 2.87 (s, 4H) 3.41-3.49(m, 4H) 3.67-3.74 (m, 4H) 4.07 (t, J=7.58 Hz, 1H) 6.97 (d, J=9.09 Hz,1H) 7.64-7.69 (m, 2H) 7.69-7.75 (m, 2H) 7.87 (d, J=8.84 Hz, 1H).

4-433-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-pyridin-3-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 591, 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.17 (t, J=7.20 Hz, 1 H)1.14 (d, J=8.34 Hz, 1 H) 1.45 (dd, J=7.33, 4.80 Hz, 2 H) 1.57 (d, J=2.27Hz, 2 H) 1.62 (d, J=7.58 Hz, 1 H) 1.72 (br. s., 2 H) 1.85 (d, J=6.82 Hz,1 H) 2.10 (s, 3 H) 2.18 (d, J=13.14 Hz, 1 H) 2.33 (d, J=3.54 Hz, 4 H)2.88 (br. s., 4 H) 4.14 (t, J=7.45 Hz, 1 H) 7.53 (dd, J=7.96, 4.67 Hz, 1H) 7.67-7.76 (m, 4 H) 8.14-8.23 (m, 3 H) 8.48 (ddd, J=8.34, 2.02, 1.77Hz, 1 H) 8.63 (dd, J=4.80, 1.77 Hz, 1 H) 9.30 (d, J=1.52 Hz, 1 H) 12.92(s, 1 H).

4-443-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-phenyl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 590, 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.20 (d, J=8.08 Hz, 2 H)1.50 (d, J=7.33 Hz, 2 H) 1.63 (d, J=4.80 Hz, 1 H) 1.68 (s, 2 H) 1.80 (s,1 H) 1.84-1.94 (m, 1 H) 2.25 (m, 1 H) 2.81 (s, 3 H) 3.20 (br. s., 2 H)3.49 (br. s., 52H) 3.80 (br. s., 2 H) 4.22 (t, J=7.58 Hz, 1 H) 7.46-7.53(m, 1 H) 7.53-7.58 (m, 2 H) 7.77-7.82 (m, 2 H) 7.82-7.87 (m, 2 H) 8.12(d, J=8.59 Hz, 1 H) 8.15-8.19 (m, 2 H) 8.22 (d, J=8.59 Hz, 1 H) 9.39(br. s., 1 H) 12.96 (s, 1 H). EC₅₀ in primary enzyme assay 0.26 μM

4-453-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-3-trifluoromethyl-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 659, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (ddd, J=19.64, 11.68,8.08 Hz, 2 H) 1.46 (dd, J=7.07, 4.55 Hz, 2 H) 1.53-1.64 (m, 3 H) 1.68(d, J=16.42 Hz, 2 H) 1.88 (ddd, J=13.52, 6.95, 6.82 Hz, 1 H) 2.24 (ddd,J=13.33, 7.83, 7.64 Hz, 1 H) 2.76 (s, 3 H) 3.11 (br. s., 1 H) 3.22 (d,J=6.32 Hz, 2 H) 3.39-3.50 (m, 2 H) 3.84 (d, J=2.53 Hz, 3 H) 4.35 (t,J=7.58 Hz, 1 H) 7.99 (dd, J=8.34, 1.26 Hz, 1 H) 8.14 (d, J=8.34 Hz, 1 H)8.10 (d, J=1.26 Hz, 1 H) 8.33 (d, J=8.59 Hz, 1 H) 8.39-8.46 (m, 1 H)8.53 (d, J=6.32 Hz, 2 H) 8.90 (d, J=6.32 Hz, 2 H) 13.21 (s, 1 H).

4-463-Cyclopentyl-N-[5-(2-methoxy-ethoxy)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 588, 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-0.89 (m, 1 H) 1.14 (br.s., 2 H) 1.25 (d, J=19.45 Hz, 2 H) 1.42 (br. s., 2 H) 1.56 (br. s., 3 H)1.71 (br. s., 2 H) 1.81 (s, 1 H) 2.73 (br. s., 2 H) 3.12 (br. s., 2 H)3.29 (s, 3 H) 3.39 (br. s., 6 H) 3.61-3.71 (m, 2 H) 3.77 (br. s., 1 H)4.12 (br. s., 1 H) 4.40 (dd, J=5.18, 3.66 Hz, 2 H) 6.91 (d, J=8.59 Hz, 1H) 7.67-7.74 (m, 2 H) 7.76-7.80 (m, 2 H) 8.02 (d, J=8.84 Hz, 1 H) 9.60(br. s., 1 H) 12.70 (br. s., 1 H).

4-474-(2-{3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazolo[5,4-b]pyridin-5-yloxy)-butyricacid: MS M+1 616, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (br. s., 2 H)1.34-1.45 (m, 2 H) 1.54 (br. s., 2 H) 1.60 (s, 1 H) 1.63-1.73 (m, 3 H)1.82 (q, J=7.07 Hz, 2 H) 1.97 (br. s., 2 H) 2.03-2.13 (m, 5 H) 2.31 (t,J=4.42 Hz, 5 H) 2.85 (br. s., 4 H) 3.65 (s, 1 H) 4.13 (t, J=6.82 Hz, 2H) 6.54 (d, J=8.59 Hz, 1 H) 7.52 (d, J=8.59 Hz, 1 H) 7.58-7.64 (m, 4 H).

4-483-Cyclopentyl-N-{5-[(2-methoxy-ethyl)-methyl-amino]-thiazolo[5,4-b]pyridin-2-yl}-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 601, 1H NMR (400 MHz, DMSO-d₆) δ ppm-1.13 (ddd, J=16.48, 11.68,8.21 Hz, 2 H) 1.39-1.49 (m, 1 H) 1.44 (dd, J=7.20, 4.67 Hz, 1 H)1.52-1.63 (m, J=15.09, 7.83, 7.61, 7.61 Hz, 3 H) 1.76 (td, J=13.58, 7.20Hz, 2 H) 1.70 (d, J=3.54 Hz, 1 H) 2.09-2.19 (m, 4 H) 2.32 (t, J=4.55 Hz,4 H) 2.87 (br. s., 4 H) 3.06 (s, 3 H) 3.24 (s, 3 H) 3.51 (d, J=11.37 Hz,1 H) 3.51 (s, 1 H) 3.71 (t, J=5.68 Hz, 2 H) 4.07 (t, J=7.45 Hz, 1 H)6.76 (d, J=9.09 Hz, 1 H) 7.64-7.69 (m, 2 H) 7.70-7.75 (m, 2H) 7.80 (d,J=9.09 Hz, 1 H) 12.40 (br. s., 1 H).

4-493-(2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazolo[5,4-b]pyridin-5-yloxy)-2,2-dimethyl-propionicacid: MS M+1 630, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.15 (m, 7 H)1.36-1.47 (m, 2 H) 1.51-1.63 (m, 3 H) 1.69 (d, J=6.06 Hz, 3 H) 2.07-2.15(m, 4 H) 2.32 (t, J=4.55 Hz, 4 H) 2.86 (br. s., 4 H) 3.31 (br. s., 3H)3.74 (br. s., 1 H) 4.14 (s, 2 H) 6.58 (d, J=8.34 Hz, 1 H) 7.57-7.66 (m,5 H).

4-503-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-[5-(4-methyl-piperazin-1-yl)-thiazolo[5,4-b]pyridin-2-yl]-propionamide:MS M+1 613, 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.14 (dd, J=11.87, 7.58 Hz,1 H) 1.10 (br. s., 1 H) 1.46 (br. s., 1 H) 1.44 (d, J=4.80 Hz, 1 H)1.52-1.63 (m, 2 H) 1.57 (d, J=4.04 Hz, 1 H) 1.69-1.81 (m, 2 H) 2.16(ddd, J=13.20, 7.83, 7.52 Hz, 1 H) 2.71 (d, J=3.54 Hz, 5 H) 2.78 (d,J=4.55 Hz, 3 H) 3.07 (d, J=11.12 Hz, 4H) 3.26-3.37 (m, 2 H) 3.38-3.50(m, 1 H) 3.74 (br. s., 2 H) 4.17 (t, J=7.45 Hz, 1 H) 4.39 (d, J=13.39Hz, 2 H) 7.09 (d, J=9.09 Hz, 1 H) 7.68-7.74 (m, 2 H) 7.74-7.81 (m, 2 H)7.95 (d, J=8.84 Hz, 1 H) 10.91 (br. s., 1 H) 11.10 (br. s., 1 H) 12.67(s, 1 H)

4-513-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-piperidin-1-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 597, 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.09-1.19 (m, 2 H) 1.45 (dd,J=7.20, 4.42 Hz, 2 H) 1.53-1.63 (m, 3 H) 1.57 (dd, J=6.69, 4.17 Hz, 7 H)1.77 (dd, J=13.52, 6.95 Hz, 2 H) 2.16 (ddd, J=13.07, 7.83, 7.64 Hz, 1H)2.63 (t, J=112.13 Hz, 2 H) 2.73 (d, J=3.79 Hz, 3 H) 3.11 (br. s., 2 H)3.43 (d, J=11.62 Hz, 2H) 3.54 (d, J=5.56 Hz, 3 H) 3.74 (br. s., 2 H)4.13 (t, J=7.58 Hz, 1 H) 6.96 (d, J=9.09 Hz, 1H) 7.69-7.74 (m, 2 H)7.77-7.83 (m, 2 H) 7.80 (d, J=4.29 Hz, 1 H) 10.37 (br. s., 1 H) 12.53(s, 1 H).

4-522-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazolo[5,4-b]pyridine-5-carboxylicacid (2-methoxy-ethyl)-methyl-amide: MS M+1 629, 1H NMR (400 MHz,DMSO-d6) δ ppm 1.15 (br. s., 2 H) 1.40-1.52 (m, 2 H) 1.57 (br. s., 3 H)1.72 (br. s., 2 H) 2.17 (s, 1 H) 2.57 (br. s., 2 H) 2.73 (br. s., 2 H)3.01 (d, J=15.16 Hz, 3 H) 3.11 (s, 3 H) 3.31 (d, J=7.33 Hz, 9 H) 3.45(d, J=5.81 Hz, 3 H) 3.59 (d, J=5.31 Hz, 1 H) 3.63 (br. s., 1 H) 3.76(br. s., 1 H) 4.18 (t, J=7.96 Hz, 1 H) 7.64 (d, J=8.34 Hz, 1 H)7.70-7.81 (m, 3 H) 8.18 (d, J=8.34 Hz, 1 H) 9.88 (br. s., 1 H) 13.03 (s,1 H). EC₅₀ in primary enzyme assay 2.1 μM

4-533-Cyclopentyl-N-[5-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 627, 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.11-1.21 (m, 2 H) 1.17 (d,J=6.06 Hz, 6 H) 1.45 (dd, J=7.33, 4.55 Hz, 2H) 1.52-1.63 (m, 2 H) 1.58(d, J=8.08 Hz, 2 H) 1.72 (br. s., 2 H) 1.78 (dd, J=13.39, 7.07 Hz, 1 H)2.16 (ddd, J=13.33, 7.83, 7.64 Hz, 1 H) 2.43 (dd, J=12.51, 10.74 Hz, 3H) 2.56-2.64 (m, 2 H) 2.73 (d, J=3.79 Hz, 3 H) 3.12 (br. s., 2 H)3.39-3.47 (m, 2 H) 3.62 (ddd, J=10.42, 6.38, 2.40 Hz, 2 H) 3.76 (d,J=12.38 Hz, 2 H) 4.13 (d, J=13.64 Hz, 2 H) 4.12 (d, J=4.55 Hz, 1H) 6.99(d, J=9.09 Hz, 1 H) 7.69-7.74 (m, 2 H) 7.79 (d, J=6.32 Hz, 2 H) 7.87 (d,J=8.84 Hz, 1 H) 10.22 (br. s., 1 H) 12.57 (s, 1 H).

4-543-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-[5-(2-methyl-pyridin-4-yl)-thiazolo[5,4-b]pyridin-2-yl]-propionamide:MS M+1 605, 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.11-1.24 (m, 2 H) 1.46 (dd,J=7.33, 4.80 Hz, 2 H) 1.59 (ddd, J=15.09, 7.39, 7.07 Hz, 3 H) 1.73 (d,J=11.62 Hz, 2 H) 1.85 (ddd, J=13.58, 7.07, 6.88 Hz, 1 H) 2.19 (ddd,J=13.20, 7.83, 7.52 Hz, 1 H) 2.67 (d, J=1.77 Hz, 1 H) 2.71 (s, 3 H) 2.80(s, 3 H) 3.14 (br. s., 2 H) 3.37-3.48 (m, 2 H) 3.70-3.82 (m, 2 H) 3.71(d, J=1.52 Hz, 1 H) 4.25 (t, J=7.58 Hz, 1 H) 7.72-7.82 (m, 4 H) 8.35 (d,J=8.34 Hz, 1 H) 8.46 (d, J=8.59 Hz, 2 H) 8.59 (s, 1 H) 8.82 (d, J=6.06Hz, 1 H) 10.71 (br. s., 1 H) 13.23 (s, 1 H).

4-553-Cyclopentyl-N-(5-ethynyl-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 538, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (t, J=7.07 Hz, 2 H)1.45 (dd, J=7.33, 4.55 Hz, 2 H) 1.53-1.64 (m, 2 H) 1.59 (d, J=7.07 Hz, 2H) 1.72 (d, J=5.05 Hz, 2 H) 1.70 (br. s., 1 H) 1.83 (ddd, J=13.39, 7.07,6.82 Hz, 1 H) 2.19 (dt, J=13.45, 7.67 Hz, 1 H) 2.76 (s, 3 H) 3.15 (br.s., 2 H) 3.44 (br. s., 2 H) 3.76 (br. s., 2 H) 4.16 (t, J=7.71 Hz, 1 H)4.42 (s, 1 H) 7.65 (d, J=8.34 Hz, 1 H) 7.71-7.75 (m, 2 H) 7.77-7.81 (m,2 H) 8.10 (d, J=8.34 Hz, 1 H) 13.01 (s, 1 H).

4-563-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-pyrimidin-5-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 593, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (d, J=7.83 Hz, 2 H)1.46 (dd, J=7.20, 4.67 Hz, 2 H) 1.53-1.65 (m, 3 H) 1.76 (br. s., 1 H)1.73 (d, J=11.62 Hz, 2 H) 1.84 (ddd, J=13.52, 6.95, 6.82 Hz, 1 H) 2.19(ddd, J=13.33, 7.83, 7.64 Hz, 1 H) 2.57-2.68 (m, 1 H) 2.67 (d, J=1.77Hz, 1 H) 2.73 (d, J=4.29 Hz, 3 H) 3.14 (br. s., 2 H) 3.42 (br. s., 2 H)3.77 (d, J=12.88 Hz, 2 H) 7.72-7.82 (m, 4 H) 8.23-8.29 (m, 2 H) 9.25 (s,1 H) 9.49 (s, 2 H) 13.05 (s, 1 H).

4-572-{3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazolo[5,4-b]pyridine-5-carboxylicacid (2-methoxy-ethyl)-amide: MS M+1 615, 1H NMR (400 MHz, DMSO-d6) δppm 1.15 (br. s., 2 H) 1.43 (br. s., 2 H) 1.52-1.63 (m, 4 H) 1.71 (br.s., 2 H) 1.83 (d, J=13.39 Hz, 1 H) 2.17 (s, 1 H) 2.75 (br. s., 3 H) 3.14(br. s., 2 H) 3.40-3.51 (m, 6 H) 3.61 (s, 3 H) 3.75 (br. s., 3 H) 4.17(s, 1 H) 7.71-7.81 (m, 4 H) 8.13 (d, J=8.59 Hz, 1 H) 8.23 (d, J=8.34 Hz,1 H) 8.76 (br. s., 1 H) 9.37 (br. s., 1 H) 13.08 (s, 1 H).

4-582-{3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazolo[5,4-b]pyridine-5-carboxylicacid dimethylamide: MS M+1 585, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15(br. s., 2 H) 1.44 (br. s., 2 H) 1.57 (br. s., 3 H) 1.72 (br. s., 2 H)1.81 (br. s., 1 H) 2.18 (br. s., 1 H) 2.74 (br. s., 3 H) 2.95 (s, 2 H)2.98-3.06 (m, 3 H) 3.12 (br. s., 2 H) 3.44 (br. s., 1 H) 3.60 (br. s., 4H) 3.74 (br. s., 2 H) 4.15 (br. s., 1 H) 7.64 (d, J=8.34 Hz, 1 H)7.70-7.82 (m, 4 H) 8.18 (d, J=8.34 Hz, 1 H) 9.32 (br. s., 1 H) 12.99 (s,1 H).

4-593-Cyclopentyl-N-[5-(2-hydroxy-ethoxy)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 574, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (br. s., 2 H) 1.43 (d,J=6.82 Hz, 2 H) 1.51-1.63 (m, 3 H) 1.73 (d, J=10.11 Hz, 2 H) 2.17 (d,J=6.06 Hz, 1 H) 2.73 (d, J=13.14 Hz, 5 H) 2.88 (s, 2 H) 3.14 (br. s., 2H) 3.43 (br. s., 2 H) 3.71 (t, J=5.05 Hz, 4 H) 4.11 (t, J=7.33 Hz, 1 H)4.29 (t, J=4.93 Hz, 2 H) 6.89 (d, J=8.84 Hz, 1 H) 7.69-7.81 (m, 4 H)8.01 (d, J=8.84 Hz, 1 H) 9.46 (br. s., 1 H) 12.69 (s, 1 H).

4-603-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 591, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (t, J=7.20 Hz, 3 H)1.54 (br. s., 1 H) 1.53 (d, J=5.05 Hz, 1 H) 1.63-1.74 (m, 2 H) 1.66 (d,J=2.27 Hz, 2 H) 1.80 (d, J=3.03 Hz, 2 H) 1.89-1.97 (m, 1 H) 2.19 (s, 3H) 2.23-2.33 (m, 1 H) 2.41 (t, J=4.42 Hz, 4 H) 2.97 (br. s., 4 H) 4.22(t, 1 H) 7.74-7.84 (m, 4 H) 8.18 (d, J=6.06 Hz, 1 H) 8.18 (d, J=3.03 Hz,1 H) 8.29 (s, 2 H) 8.79 (d, J=6.06 Hz, 1 H) 8.79 (d, J=3.03 Hz, 1 H)13.06 (br. s., 1 H).

4-613-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-[5-(morpholine-4-carbonyl)-thiazolo[5,4-b]pyridin-2-yl]-propionamide:MS M+1 627, 1H NMR (400 MHz, DMSO-d6) δ ppm 0.90-1.00 (m, 1 H) 0.94 (d,J=7.58 Hz, 1 H) 1.25 (br. s., 1 H) 1.23 (d, J=4.80 Hz, 1 H) 1.32-1.44(m, 1 H) 1.38 (d, J=13.39 Hz, 2 H) 1.51 (d, J=11.62 Hz, 2 H) 1.63 (d,J=6.82 Hz, 1 H) 1.93-2.02 (m, 1 H) 1.98 (d, J=13.39 Hz, 1 H) 2.32 (br.s., 2 H) 2.53 (br. s., 3 H) 2.92 (br. s., 2 H) 3.23-3.30 (m, 4 H) 3.35(d, J=5.81 Hz, 2 H) 3.41-3.51 (m, 4H) 3.98 (t, J=7.58 Hz, 1 H) 7.47-7.55(m, 1 H) 7.49 (d, J=8.34 Hz, 2 H) 7.56-7.62 (m, 2 H) 8.00 (d, J=8.34 Hz,1 H) 9.73 (br. s., 1 H) 12.83 (s, 1 H).

4-623-Cyclopentyl-N-(5-isopropoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 572, 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.89 (m, 1 H) 1.14 (br.s., 2 H) 1.22-1.32 (m, 6 H) 1.44 (dd, J=7.07, 4.55 Hz, 2 H) 1.51-1.63(m, 3 H) 1.71 (br. s., 1 H) 1.74-1.83 (m, 1 H) 2.11-2.21 (m, 1 H) 2.72(br. s., 2 H) 3.11 (br. s., 2 H) 3.41 (br. s., 3 H) 3.46 (br. s., 2 H)3.73 (br. s., 2 H) 4.09-4.17 (m, 1 H) 5.20-5.29 (m, J=6.19, 6.19, 6.19,6.19 Hz, 1 H) 6.82 (d, J=8.84 Hz, 1 H) 7.66-7.73 (m, 2H) 7.75-7.80 (m, 2H) 7.99 (d, J=8.84 Hz, 1 H) 10.02 (br. s., 1 H) 12.69 (s, 1 H).

4-63N-(5-Benzyl-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 604, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.20 (m, 1 H) 1.15 (t,J=7.20 Hz, 2 H) 1.44 (ddd, J=11.81, 7.14, 6.82 Hz, 3 H) 1.52-1.61 (m, 1H) 1.57 (d, J=4.29 Hz, 2 H) 1.66-1.76 (m, 1 H) 1.71 (d, J=9.35 Hz, 2 H)1.80 (dd, J=13.52, 6.95 Hz, 1 H) 2.17 (ddd, J=13.26, 7.96, 7.83 Hz, 1 H)2.62 (t, J=12.25 Hz, 1 H) 2.72 (d, J=3.79 Hz, 2 H) 3.14 (br. s., 2 H)3.39-3.48 (m, 1 H) 3.42 (d, J=12.13 Hz, 1 H) 3.70-3.81 (m, 1 H) 3.76 (d,J=12.88 Hz, 1 H) 4.18 (s, 2 H) 7.20 (dd, J=9.22, 4.42 Hz, 1 H) 7.29 (d,J=1.26 Hz, 1 H) 7.26-7.31 (m, 2 H) 7.37 (d, J=8.34 Hz, 1 H) 7.70-7.75(m, 2 H) 7.75-7.81 (m, 2 H) 8.02 (d, J=8.34 Hz, 1 H) 10.34 (br. s., 1 H)12.84 (s, 1 H).

4-64N-(5-Amino-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 529, 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.13 (s, 2 H) 1.49 (s,2 H) 1.62 (s, 3 H) 1.74 (s, 2 H) 1.91 (s, 1 H) 2.26 (s, 4 H) 2.48 (s, 4H) 3.06 (s, 4 H) 3.66 (s, 1 H) 4.54 (s, 2 H) 6.57 (d, J=8.72 Hz, 1 H)7.49-7.54 (m, 2 H) 7.71 (d, J=8.72 Hz, 1 H) 7.74 (d, J=8.46 Hz, 2 H).

4-653-Cyclopentyl-N-[5-(2-methoxy-ethylamino)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 587, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.24 (s, 2 H) 1.49-1.58 (m,2 H) 1.66 (s, 3 H) 1.86 (d, J=6.82 Hz, 3 H) 2.25 (d, J=12.51 Hz, 1 H)2.53 (s, 2 H) 2.85 (s, 3 H) 3.26 (d, J=13.89 Hz, 2 H) 3.36 (s, 3 H)3.48-3.59 (m, 5H) 3.84 (s, 2 H) 4.15-4.22 (m, 1 H) 6.72 (d, J=8.97 Hz, 1H) 7.76-7.84 (m, 3 H) 7.85-7.90 (m, 2 H).

4-662-[3-Chloro-4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-chloro-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-propionamide:MS M+1 582, 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-0.91 (m, 1 H) 1.15 (br.s., 2 H) 1.23 (br. s., 2 H) 1.44 (br. s., 2 H) 1.58 (br. s., 2H) 1.63(br. s., 1 H) 1.72 (br. s., 2 H) 1.77-1.88 (m, 1 H) 2.15 (br. s., 1 H)2.78 (br. s., 2 H) 3.09 (br. s., 4 H) 3.45 (br. s., 1 H) 3.85 (br. s., 1H) 4.14 (br. s., 1 H) 7.55-7.65 (m, 2 H) 7.76 (s, 1 H) 8.00 (d, J=8.34Hz, 1 H) 8.18 (d, J=8.59 Hz, 13H) 10.08 (br. s., 1 H) 13.03 (s, 1H).

4-67N-(5-Bromo-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-3-trifluoromethyl-phenyl]-propionamide:MS M+1 661, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.07-1.16 (m, 2 H) 1.39-1.49(m, 2 H) 1.52-1.64 (m, 3 H) 1.65-1.75 (m, 2 H) 1.80-1.89 (m, 1 H) 2.16(s, 3 H) 2.18-2.25 (m, 1 H) 2.31-2.37 (m, 4 H) 3.14-3.20 (m, 4H) 4.20(t, J=7.58 Hz, 1 H) 7.68 (d, J=8.34 Hz, 1 H) 7.92 (dd, J=8.34, 1.52 Hz,1 H) 8.01-8.04 (m, 1 H) 8.04-8.08 (m, 2 H).

4-683-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-3-trifluoromethyl-phenyl]-N-[5-(4-methyl-piperazin-1-yl)-thiazolo[5,4-b]pyridin-2-yl]-propionamide:MS M+1 680, 1H NMR (400 MHz, DMSO-d6) δppm 1.09-1.21 (m, 2 H) 1.45 (dd,J=7.33, 4.55 Hz, 2 H) 1.52-1.64 (m, 3H) 1.70 (d, J=16.93 Hz, 2 H) 1.82(dt, J=13.45, 6.79 Hz, 1 H) 2.20 (t, J=14.40 Hz, 1 H) 2.20 (d, J=13.64Hz, 1 H) 2.77 (br. s., 3 H) 2.81 (d, J=4.80 Hz, 3 H) 3.09 (br. s., 4 H)3.15 (br. s., 3 H) 3.26 (br. s., 3 H) 3.39 (br. s., 4 H) 3.83 (br. s., 2H) 4.24 (t, J=7.58 Hz, 1 H) 4.40 (d, J=14.40 Hz, 2 H) 7.09 (d, J=9.35Hz, 1 H) 7.96 (d, J=8.84 Hz, 2 H) 8.06 (d, J=1.52 Hz, 1 H) 8.12 (d,J=8.34 Hz, 1 H).

4-692-[3-Chloro-4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-3-cyclopentyl-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 625, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15 (d, J=11.62 Hz, 2 H)1.23 (s, 1 H) 1.40-1.50 (m, 2 H) 1.53-1.65 (m, 3 H) 1.75 (d, J=10.61 Hz,2 H) 1.81-1.90 (m, 1 H) 2.13-2.24 (m, 1 H) 2.78 (s, 3 H) 3.12 (d, J=6.32Hz, 3H) 3.43 (br. s., 3 H) 3.85 (br. s., 2 H) 4.20 (t, J=7.58 Hz, 1 H)7.64 (dd, J=8.34, 1.77 Hz, 1 H) 7.78 (d, J=1.52 Hz, 1 H) 8.01 (d, J=8.08Hz, 1 H) 8.27-8.35 (m, 1 H) 8.37-8.47 (m, 3 H) 8.86 (d, J=6.57 Hz, 2 H)10.52 (br. s., 1 H) 13.13 (s, 1 H).

4-703-Cyclopentyl-N-[5-(2-cyclopropyl-pyridin-4-yl)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 631, 1H NMR (400 MHz, DMSO-D6) δ ppm 0.94-1.00 (m, 4 H) 1.09-1.19(m, 2 H) 1.39-1.50 (m, 2 H) 1.53-1.64 (m, 3 H) 1.72 (d, J=11.62 Hz, 2 H)1.84 (ddd, J=13.64, 7.20, 6.95 Hz, 1 H) 2.10 (s, 3 H) 2.17-2.28 (m, 2 H)2.33 (s, 4 H) 2.88 (s, 4 H) 4.15 (t, J=7.58 Hz, 1 H) 7.67-7.72 (m, 2 H)7.72-7.76 (m, 2 H) 7.81 (dd, J=5.31, 1.77 Hz, 1 H) 8.01 (s, 1 H)8.19-8.24 (m, 2 H) 8.50 (d, J=5.30 Hz, 1 H).

4-71N-(5-Chloro-thiazolo[5,4-b]pyridin-2-yl)-3-cyclohexyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 563, 1H NMR (400 MHz, DMSO-D6) δ ppm 0.88-1.00 (m, 2 H) 1.06-1.17(m, 6 H) 1.55-1.81 (m, 5 H) 2.05-2.12 (m, 1 H) 2.72 (s, 4 H) 3.13 (m, 1H) 3.38 (m, 4 H) 3.74 (m, 1 H) 4.28 (t, J=7.0 Hz, 1 H) 7.57 (d, J=8.6Hz, 1 H) 7.71 (d, J=8.5 Hz, 2 H) 7.79 (d, J=8.5 Hz, 2 H) 8.17 (d, J=8.6Hz, 1H).

4-722-[3-Chloro-4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-3-cyclopentyl-N-[5-(4-methyl-piperazin-1-yl)-thiazolo[5,4-b]pyridin-2-yl]-propionamide:MS M+1 646, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.19 (m, 2H) 1.39-1.49(m, 2H) 1.53-1.62 (m, 3H) 1.65-1.75 (m, 2H) 1.76-1.84 (m, 1H) 2.09-2.20(m, 1H) 2.81 (s, 3H) 2.86 (s, 3H) 2.9-3.2 (m, 8H) 3.42-3.9 (m, 6H)4.05-4.13 (m, 1H) 4.36-4.47 (m, 2H) 7.09 (d, J=8.43 Hz, 1H) 7.61 (dd,J=8.43 Hz, 1.77 Hz, 1H) 7.74 (s, 1H) 7.94-8.01 (m, 2H).

4-73(S)-4-{4-[2-Cyclopentyl-1-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-1-methyl-piperazine-2-carboxylicacid: MS M+1 635, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (d, J=8.34 Hz, 2H) 1.45 (dd, J=7.33, 4.80 Hz, 2 H) 1.58 (d, J=5.05 Hz, 2 H) 1.62 (d,J=7.33 Hz, 1 H) 1.73 (br. s., 2 H) 1.80-1.88 (m, 1 H) 2.18 (s, 1 H) 2.69(s, 3 H) 2.99 (br. s., 1 H) 3.36 (br. s., 2 H) 3.54 (br. s., 1 H) 3.97(br. s., 1 H) 4.12-4.22 (m, 1 H) 7.72 (d, J=8.34 Hz, 2 H) 7.79-7.84 (m,2 H) 8.25-8.33 (m, 4 H) 8.79 (d, J=6.32 Hz, 1 H) 13.04 (s, 1 H).

4-743-Cyclopentyl-2-[4-((S)-3,4-dimethyl-piperazine-1-sulfonyl)-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 605, 1H NMR (400 MHz, DMSO-d6)□ ppm 0.92 (d, J=6.06 Hz, 3 H)1.10-1.20 (m, 3 H) 1.39-1.48 (m, 2 H) 1.53-1.65 (m, 1 H) 1.66-1.75 (m, 2H) 1.79-1.88 (m, 1 H) 1.99 (s, 2 H) 2.00-2.07 (m, 1 H) 2.11-2.23 (m, 2H)2.30-2.40 (m, 1 H) 2.66-2.74 (m, 1 H) 3.28-3.32 (m, 3 H) 3.34-3.42 (m, 2H) 4.15 (t, J=7.58 Hz, 1 H) 7.67-7.76 (m, 4 H) 8.05-8.12 (m, 2 H) 8.23(s, 2 H) 8.66-8.72 (m, 2 H) 12.98 (br. s., 1 H).

4-753-Cyclopentyl-2-[4-((S)-3,4-dimethyl-piperazine-1-sulfonyl)-phenyl]-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 613, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (br. s., 2 H) 1.25 (d,J=6.32 Hz, 3 H) 1.44 (d, J=4.55 Hz, 2 H) 1.52-1.63 (m, 3 H) 1.74 (d,J=11.37 Hz, 2 H) 1.79 (d, J=5.31 Hz, 1 H) 2.09-2.18 (m, 1 H) 2.20 (br.s., 1 H) 2.40 (br. s., 1 H) 2.59-2.68 (m, 2 H) 2.74 (d, J=4.55 Hz, 6 H)3.21 (d, J=3.79 Hz, 1 H) 3.39 (br. s., 1 H) 3.40-3.51 (m, 5 H) 3.66-3.74(m, 4 H) 4.09-4.16 (m, 1 H) 6.98 (d, J=9.09 Hz, 1H) 7.71 (d, J=8.59 Hz,2 H) 7.75-7.81 (m, 2 H) 7.88 (d, J=9.09 Hz, 1 H) 12.57 (s, 1 H).

4-76(S)-4-{4-[2-Cyclopentyl-1-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-1-methyl-piperazine-2-carboxylicacid methyl ester: MS M+1 649, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (br.s., 2 H) 1.18 (t, J=7.07 Hz, 1 H) 1.42 (br. s., 1 H) 1.45 (dd, J=7.20,4.67 Hz, 1 H) 1.52-1.62 (m, 1 H) 1.63 (s, 1 H) 1.70 (br. s., 1 H) 1.72(d, J=5.31 Hz, 1 H) 1.79-1.89 (m, 1 H) 2.15-2.24 (m, 3 H) 2.34 (d,J=7.33 Hz, 1 H) 2.87 (br. s., 1 H) 2.92-3.00 (m, 2 H) 3.08 (d, J=3.28Hz, 1 H) 3.18 (dd, J=6.69, 3.41 Hz, 1 H) 3.27-3.33 (m, 2 H) 3.62 (s, 3H) 4.15 (s, 1 H) 7.69 (s, 1 H) 7.71 (d, J=1.26 Hz, 1 H) 7.72-7.78 (m, 2H) 8.06-8.12 (m, 2 H) 8.24 (s, 2 H) 8.66-8.72 (m, 2 H) 12.97 (s, 1 H).

4-77(R)-4-{4-[2-Cyclopentyl-1-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-1-methyl-piperazine-2-carboxylicacid methyl ester: MS M+1 649, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t,J=7.20 Hz, 3 H) 1.43 (br. s., 1 H) 1.45 (d, J=2.53 Hz, 1H) 1.57 (br. s.,2 H) 1.63 (s, 1 H) 1.72 (br. s., 2 H) 1.80-1.89 (m, 1 H) 2.15-2.24 (m, 4H) 2.29-2.36 (m, 1 H) 2.94 (d, J=7.58 Hz, 3 H) 3.08 (br. s., 1 H) 3.18(dd, J=6.69, 3.41 Hz, I H) 3.29 (s, 4 H) 3.62 (s, 3 H) 4.12-4.18 (m, 1H) 7.66-7.72 (m, 2 H) 7.73-7.77 (m, 2 H) 8.08-8.12 (m, 2 H) 8.23 (s, 2H) 8.66-8.72 (m, 2 H) 12.97 (s, 1 H).

4-78(R)-4-{4-[2-Cyclopentyl-1-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-1-methyl-piperazine-2-carboxylicacid: MS M+1 635, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.22 (m, 2 H)1.45 (dd, J=7.33, 4.80 Hz, 2 H) 1.56 (br. s., 1 H) 1.57-1.60 (m, 1 H)1.60-1.65 (m, 1 H) 1.68-1.78 (m, 2 H) 1.84 (ddd, J=13.58, 7.07, 6.88 Hz,1H) 2.20 (ddd, J=13.52, 7.83, 7.45 Hz, 1 H) 2.75 (s, 3 H) 2.88 (br. s.,1 H) 3.10 (br. s., 1 H) 3.43 (br. s., 2 H) 3.58 (br. s., 1 H) 4.18 (t,J=7.45 Hz, 2 H) 7.73 (d, J=8.34 Hz, 2 H) 7.79-7.86 (m, 2 H) 8.28-8.32(m, 1 H) 8.33-8.40 (m, 39H) 8.83 (d, J=6.32 Hz, 2 H) 13.08 (s, 1H).

4-792-{(R)-3-Cyclopentyl-2-[4-(2-methoxy-ethylsulfamoyl)-phenyl]-propionylamino}-benzothiazole-6-carboxylicacid: MS M+1 533, 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.16 (m, 2 H)1.41 (dd, J=7.07, 4.80 Hz, 1 H) 1.38 (br. s., 1 H) 1.57 (br. s., 1 H)1.54 (dd, J=6.19, 2.65 Hz, 1 H) 1.63 (br. s., 1 H) 1.60 (d, J=7.33 Hz, 2H) 1.72 (br. s., 1 H) 1.68 (dd, J=13.14, 6.32 Hz, 8 H) 2.04-2.12 (m, 1H) 2.07 (s, 3 H) 2.85 (t, J=5.94 Hz, 2 H) 3.13 (s, 3H) 3.26 (t, J=5.94Hz, 2 H) 3.60 (t, J=7.58 Hz, 1 H) 7.13 (d, J=8.34 Hz, 1 H) 7.54 (d,J=8.34 Hz, 3 H) 7.60-7.67 (m, 3 H) 7.99 (d, J=1.52 Hz, 1 H).

4-802-((R)-3-Cyclopentyl-2-{4-[(2-methoxy-ethyl)-methyl-sulfamoyl]-phenyl}-propionylamino)-benzothiazole-6-carboxylicacid: MS M+1 547, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.04-1.16 (m, 2 H)1.35-1.47 (m, 2 H) 1.52-1.59 (m, 2 H) 1.62-1.72 (m, 3 H) 2.05-2.15 (m, 1H) 2.07 (s, 3 H) 2.86 (s, 3 H) 3.10 (t, J=5.68 Hz, 2 H) 3.19 (s, 3 H)3.41 (t, J=5.56 Hz, 2 H) 3.62 (t, J=7.45 Hz, 1 H) 7.13 (d, J=8.59 Hz, 1H) 7.59-7.66 (m, 4 H) 7.99 (m, 1 H).

4-81(R)—N-(5-Chloro-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(2-methoxy-ethylsulfamoyl)-phenyl]-propionamide:MS M+1 523, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.20 (m, 2 H) 1.38-1.48(m, 2 H) 1.51-1.62 (m, 3 H) 1.70 (br. s., 2 H) 1.75-1.86 (m, 1 H)2.10-2.20 (m, 1 H) 2.89 (q, J=5.73 Hz, 2 H) 3.09 (s, 3 H) 3.25 (t,J=5.81 Hz, 2 H) 4.09 (t, J=7.58 Hz, 1 H) 7.58 (dd, J=17.18, 8.34 Hz, 3H) 7.69 (t, J=5.81 Hz, 1 H) 7.78 (d, J=8.59 Hz, 2 H) 8.15 (d, J=8.34 Hz,1 H) 12.95 (s, 1 H).

4-82N-(5-Bromo-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(4-methyl-4,7-diaza-spiro[2.5]octane-7-sulfonyl)-phenyl]-propionamide:MS M+1 619, 1H NMR (400 MHz, DMSO-d6) δppm 0.44 (d, J=10.86 Hz, 1 H)0.44 (d, J=1.77 Hz, 1 H) 0.58 (d, J=10.86 Hz, 1 H) 0.58 (d, J=1.52 Hz, 1H) 1.12 (td, J=8.21, 4.80 Hz, 2 H) 1.05-1.15 (m, 1 H) 1.43 (dd, J=7.33,4.80 Hz, 2 H) 1.51-1.62 (m, 3 H) 1.69 (dd, J=11.49, 4.93 Hz, 2 H) 1.82(t, J=13.89 Hz, 1 H) 1.82 (d, J=13.39 Hz, 1 H) 2.03 (s, 3 H) 2.17 (ddd,J=13.33, 7.58, 7.39 Hz, 1 H) 2.73 (s, 2 H) 2.79 (d, J=5.56 Hz, 2 H) 2.77(br. s., 1 H) 2.90 (d, J=5.81 Hz, 2 H) 4.11 (t, J=7.58 Hz, 1 H) 7.68 (d,J=2.78 Hz, 2 H) 7.66 (d, J=2.78 Hz, 1 H) 7.71-7.75 (m, 2 H) 8.04 (d,J=8.59 Hz, 1H).

4-833-Cyclopentyl-2-[4-(4-methyl-4,7-diaza-spiro[2.5]octane-7-sulfonyl)-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 617, 1H NMR (400 MHz, DMSO-d6) δ ppm 0.44 (d, J=10.86 Hz, 1 H)0.44 (d, J=1.77 Hz, 1 H) 0.58 (d, J=10.86 Hz, 1H) 0.58 (d, J=1.52 Hz, 1H) 1.12 (td, J=8.21, 4.80 Hz, 2 H) 1.05-1.15 (m, 1 H) 1.43 (dd, J=7.33,4.80 Hz, 2 H) 1.51-1.62 (m, 3 H) 1.69 (dd, J=11.49, 4.93 Hz, 2 H) 1.82(t, J=13.89 Hz, 1 H) 1.82 (d, J=13.39 Hz, 1 H) 1.99 (s, 1 H) 2.17 (ddd,J=13.33, 7.58, 7.39 Hz, 1 H) 2.73 (s, 2 H) 2.79 (d, J=5.56 Hz, 2 H) 2.77(br. s., 1 H) 2.90 (d, J=5.81 Hz, 2 H) 4.11 (t, J=7.58 Hz, 1 H) 7.68 (d,J=2.78 Hz, 2 H) 7.66 (d, J=2.78 Hz, 1 H) 7.71-7.75 (m, 2 H) 8.04 (d,J=8.59 Hz, 1 H).

4-843-Cyclopentyl-2-[4-(4-methyl-4,7-diaza-spiro[2.5]octane-7-sulfonyl)-phenyl]-N-[5-(4-methyl-piperazin-1-yl)-thiazolo[5,4-b]pyridin-2-yl]-propionamide:MS M+1 638, 1H NMR (400 MHz, DMSO-d6) δ ppm 0.70-1.2 (m, 6H) 1.38-1.49(m, 2H) 1.52-1.63 (m, 3H) 1.67-1.83 (m, 3H) 2.11-2.21 (m, 1H) 2.85 (s,3H) 3.12-3.64 (m, 4H) 4.05-4.15 (m, 1H) 4.36-4.46 (m, 2H) 7.09 (d,J=9.09 Hz, 1H) 7.66-7.72 (m, 2H) 7.96 (d, J=9.09 Hz, 1H).

4-85(R)-3-Cyclopentyl-2-[4-(4-methyl-4,7-diaza-spiro[2.5]octane-7-sulfonyl)-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 617, 1H NMR (400 MHz, DMSO-d6) δ ppm 0.41-0.46 (m, 2H) 0.55-0.60(m, 2H) 1.38-1.48 (m, 3H) 1.54-1.63 (m, 3H) 1.67-1.75 (m, 3H) 1.80-1.88(m, 1H) 2.12 (s, 3H) 2.14-2.24 (m, 1H) 2.73 (s, 2H) 2.77-2.80 (m, 2H)2.88-2.94 (m, 2H) 4.12-4.18 (m, 1H) 7.67-7.72 (m, 2H) 7.74-7.78 (m, 2H)8.08-8.12 (m, 2H) 8.23 (s, 2H) 8.68-8.72 (m, 2H).

4-863-Cyclopentyl-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(3,3,4-trimethyl-piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 619, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (br. s., 2 H) 1.30 (d,J=7.58 Hz, 6 H) 1.45 (d, J=2.53 Hz, 2 H) 1.59 (br. s., 3 H) 1.74 (br.s., 2 H) 1.83 (br. s., 1 H) 2.19 (br. s., 1 H) 2.41 (br. s., 2 H) 2.67(br. s., 3 H) 3.33-3.44 (m, 2 H) 3.63 (br. s., 4 H) 4.18 (br. s., 1 H)7.72-7.83 (m, 4 H) 8.22-8.33 (m, 4 H) 8.77 (d, J=5.05 Hz, 2 H) 9.47 (br.s., 1 H) 13.04 (s, 1H).

4-872-(4-Butyrylsulfamoyl-phenyl)-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 531, 1H NMR (400 MHz, DMSO-D6) δ ppm 0.75 (t, J=7.45 Hz, 4 H)1.13 (s, 3 H) 1.36-1.47 (m, 5 H) 1.52-1.63 (m, 5 H) 1.76 (ddd, J=13.52,6.95, 6.82 Hz, 5H) 1.82 (s, 1 H) 1.85 (t, J=7.33 Hz, 4 H) 2.09 (ddd,J=13.26, 7.71, 7.58 Hz, 2 H) 3.87-3.93 (m, 6 H) 6.84 (d, J=8.84 Hz, 2 H)7.33-7.36 (m, 3 H) 7.63-7.67 (m, 3 H).

4-883-Cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-{4-[4-(2-oxo-2-piperidin-1-yl-ethyl)-piperazine-1-sulfonyl]-phenyl}-propionamide:MS M+1 655, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.23 (br. s., 5 H) 1.41 (br.s., 4 H) 1.55 (br. s., 3 H) 1.70 (br. s., 2 H) 2.44 (br. s., 6 H) 2.84(br. s., 4 H) 3.07 (s, 2 H) 3.24 (br. s., 4 H) 3.90 (s, 3 H) 4.05 (s, 2H) 6.91 (s, 1 H) 7.70 (d, J=14.15 Hz, 4 H) 8.02 (s, 1 H) 12.63 (s, 1 H).

4-893-Cyclopentyl-2-{4-[4-(isopropylcarbamoyl-methyl)-piperazine-1-sulfonyl]-phenyl}-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 629, 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95 (d, J=6.57 Hz, 6 H)1.11 (d, J=3.54 Hz, 1 H) 1.44 (dd, J=7.20, 4.67 Hz, 2 H) 1.51-1.63 (m, 4H) 1.68-1.76 (m, 2 H) 2.13-2.20 (m, 1 H) 2.45 (br. s., 2 H) 2.46 (d,J=4.55 Hz, 3 H) 2.83 (s, 2 H) 2.93 (br. s., 4 H) 3.80 (dd, J=14.65, 6.82Hz, 1 H) 3.90 (s, 3 H) 4.09 (d, J=14.91 Hz, 1 H) 6.90 (d, J=8.84 Hz, 1H) 7.37 (d, J=8.08 Hz, 1 H) 7.65-7.69 (m, 2H) 7.72-7.76 (m, 2 H) 8.02(d, J=8.84 Hz, 1 H) 12.66 (br. s., 1 H).

1-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperidine-4-carboxylicacid: MS M+1 573, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.05-1.16 (m, 2 H)1.36-1.47 (m, 2 H) 1.49-1.61 (m, 5 H) 1.66-1.72 (m, 3 H) 1.75 (s, 1 H)1.78-1.80 (m, 1 H) 1.92-2.02 (m, 1 H) 2.08-2.18 (m, 1 H) 2.40 (t, J=9.85Hz, 2 H) 3.35 (d, J=11.37 Hz, 2 H) 3.82-3.92 (m, 4 H) 6.74 (d, J=8.59Hz, 1 H) 7.59-7.67 (m, 4 H) 7.79 (d, J=8.84 Hz, 1 H).

4-901-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperidine-3-carboxylicacid: MS M+1 573, 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.08 (br. s., 2H) 1.18 (t, J=7.20 Hz, 1 H) 1.42 (br. s., 3 H) 1.54 (br. s., 2 H) 1.66(d, J=14.15 Hz, 2 H) 1.61 (d, J=7.83 Hz, 2 H) 1.78 (br. s., 1 H) 1.83(dd, J=13.26, 6.69 Hz, 1 H) 1.89-2.00 (m, 1 H) 2.23 (d, J=6.32 Hz, 1 H)2.65 (br. s., 2 H) 2.77 (br. s., 1 H) 3.41 (s, 1 H) 3.78 (d, J=6.06 Hz,2 H) 3.91 (s, 4 H) 6.71 (dd, J=8.72, 3.41 Hz, 1H) 7.55 (t, J=7.45 Hz, 2H) 7.65 (dd, J=8.21, 4.93 Hz, 1 H) 7.71 (br. s., 2 H).

4-91((S)-1-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-pyrrolidin-2-yl)-aceticacid: MS M+1 573, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (br. s., 2 H)1.39 (br. s., 4 H) 1.54 (br. s., 4 H) 1.70 (br. s., 4 H) 2.11 (br. s., 2H) 3.05 (br. s., 1 H) 3.26 (br. s., 3 H) 3.85 (s, 5 H) 6.71 (s, 1 H)7.63 (s, 2 H) 7.70 (s, 2 H) 7.75 (s, 1 H).

4-924-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperazine-2-carboxylicacid: MS M+1 574, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05-1.17 (m, 1 H)1.11 (d, J=4.29 Hz, 1 H) 1.42 (dd, J=7.07, 4.80 Hz, 2 H) 1.51-1.63 (m, 3H) 1.70 (dd, J=12.88, 6.57 Hz, 3 H) 1.88 (t, J=10.74 Hz, 1 H) 2.02-2.14(m, 2 H) 2.58 (t, J=11.75 Hz, 1 H) 2.76 (d, J=9.60 Hz, 1 H) 2.89 (d,J=11.87 Hz, 1 H) 3.63 (d, J=10.11 Hz, 1 H) 3.81 (d, J=7.58 Hz, 1 H) 3.85(s, 3 H) 6.68 (d, J=8.59 Hz, 1 H) 7.57-7.66 (m, 4 H) 7.71 (d, J=8.08 Hz,1 H).

4-931-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-4-methyl-piperazine-2-carboxylicacid: MS M+1 588, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (br. s., 2 H)1.43 (d, J=4.80 Hz, 2 H) 1.60 1.57 (t, J=7.58 Hz, 3 H) 1.78 (dd,J=13.77, 6.95 Hz, 3 H) 2.15 (d, J=13.64 Hz, 2 H) 3.91 (s, 5 H) 4.08-4.19(m, 2 H) 4.45 (br. s., 2 H) 6.91 (d, J=8.84 Hz, 1 H) 7.62 (d, J=8.08 Hz,2 H) 7.81 (d, J=8.34 Hz, 2 H) 8.03 (d, J=8.59 Hz, 1 H) 12.72 (s, 1 H).

4-941-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperazine-2-carboxylicacid: MS M+1 574, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08-1.19 (m, 2 H)1.13 (dd, J=11.24, 5.43 Hz, 2 H) 1.44 (dd, J=7.20, 4.67 Hz, 2 H)1.51-1.63 (m, 3 H) 1.73 (td, J=14.21, 6.95 Hz, 3 H) 2.15 (d, J=12.88 Hz,1 H) 2.42 (td, J=11.94, 3.41 Hz, 1 H) 2.68 (dd, J=12.13, 4.29 Hz, 1 H)2.83 (d, J=11.12 Hz, 1 H) 3.38 (br. s., 2 H) 3.52 (s, 1 H) 3.91 (s, 3 H)4.07 (t, J=7.58 Hz, 1 H) 4.30 (d, J=3.28 Hz, 1 H) 6.91 (d, J=8.84 Hz, 1H) 7.57 (d, J=7.83 Hz, 2 H) 7.79 (d, J=8.34 Hz, 2 H) 8.02 (d, J=8.59 Hz,1 H). EC₅₀ in primary enzyme assay 9.3 μM

4-951-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-pyrrolidine-3-carboxylicacid: MS M+1 559, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (br. s., 3 H)1.43 (br. s., 3 H) 1.54 (br. s., 3 H) 1.73 (s, 5 H) 2.13 (br. s., 1 H)3.07 (s, 2 H) 3.21 (s, 2 H) 3.87 (s, 4 H) 3.96 (br. s., 1 H) 6.79 (s, 1H) 7.61 (s, 2 H) 7.71 (s, 2 H) 7.85 (s, 1 H).

4-964-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-1-methyl-piperazine-2-carboxylicacid: MS M+1 588, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07-1.19 (m, 2 H)1.44 (dd, J=7.33, 4.80 Hz, 2 H) 1.58 (dq, J=15.22, 7.64 Hz, 2 H) 1.56(br. s., 2 H) 1.70 (dd, J=6.82, 4.55 Hz, 2 H) 1.81 (ddd, J=13.58, 7.07,6.88 Hz, 1 H) 2.16 (ddd, J=13.26, 7.71, 7.58 Hz, 1 H) 2.31 (s, 3 H) 2.42(t, J=8.21 Hz, 1 H) 2.75 (t, J=8.08 Hz, 1 H) 2.83 (dd, J=10.86, 7.83 Hz,1 H) 2.98-3.10 (m, 3 H) 3.19 (d, J=11.12 Hz, 1 H) 3.91 (s, 3 H) 4.10 (t,J=7.58 Hz, 1 H) 6.91 (d, J=8.59 Hz, 1 H) 7.66-7.71 (m, 2 H) 7.73-7.78(m, 2 H) 8.03 (d, J=8.84 Hz, 1 H) 12.68 (s, 1 H).

4-97{2-[3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-propionylamino]-thiazolo[5,4-b]pyridin-5-yloxy}-aceticacid: MS M+1 561, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.07 Hz, 6H) 1.07-1.18 (m, 2 H) 1.43 (dd, J=7.20, 4.67 Hz, 2 H) 1.56 (t, J=7.33Hz, 3 H) 1.69 (d, J=6.32 Hz, 2 H) 1.79 (ddd, J=13.58, 7.07, 6.88 Hz, 1H) 2.15 (dd, J=7.20, 5.43 Hz, 1 H) 3.14 (q, J=7.07 Hz, 4 H) 4.07 (t,J=7.58 Hz, 1 H) 4.88 (s, 2 H) 6.99 (d, J=8.84 Hz, 1 H) 7.61 (d, J=8.34Hz, 2 H) 7.78 (d, J=8.59 Hz, 2 H) 8.06 (d, J=8.84 Hz, 1 H) 12.68 (br.s., 1 H).

4-98N-(5-Carbamoylmethoxy-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-propionamide:MS M+1 560, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03 (t, J=7.20 Hz, 6 H)1.12 (d, J=11.62 Hz, 2 H) 1.43 (dd, J=7.07, 4.80 Hz, 2 H) 1.59 (br. s.,1 H) 1.57 (d, J=7.33 Hz, 2 H) 1.70 (br. s., 2 H) 1.79 (ddd, J=13.58,7.07, 6.88 Hz, 1 H) 2.13 (t, J=7.58 Hz, 1 H) 3.14 (q, J=7.07 Hz, 4 H)4.07 (t, J=7.58 Hz, 1 H) 4.71 (s, 2 H) 6.99 (d, J=8.84 Hz, 1 H)7.18-7.27 (m, 1 H) 7.50 (br. s., 1 H) 7.61 (d, J=8.34 Hz, 2 H) 7.78 (d,J=8.34 Hz, 2 H) 8.06 (d, J=8.84 Hz, 1 H) 12.68 (s, 1 H).

4-993-(4-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonylamino}-piperidin-1-yl)-propionicacid: MS M+1 617

4-100(R)-1-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperidine-2-carboxylicacid: MS M+1 573, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (br. s., 4 H)1.23 (br. s., 2 H) 1.38 (br. s., 5 H) 1.70 (br. s., 4 H) 2.06 (br. s., 3H) 3.45 (br. s., 1 H) 3.87 (s, 5 H) 4.05 (br. s., 1 H) 6.77 (br. s., 1H) 7.50 (s, 3 H) 7.82 (br. s., 3H).

4-101(S)-1-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperidine-2-carboxylicacid: MS M+1 573, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (br. s., 3 H)1.22 (br. s., 2 H) 1.35 (br. s., 5 H) 1.55 (br. s., 4 H) 1.69 (br. s., 4H) 2.09 (br. s., 3 H) 3.87 (s, 4 H) 4.05 (br. s., 1 H) 6.78 (br. s., 1H) 7.50 (s, 2 H) 7.81 (br. s., 3H).

4-1023-(4-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperazin-1-yl)-propionicacid: MS M+1 602, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (br. s., 3 H)1.55 (br. s., 4 H) 1.71 (br. s., 4 H) 2.09-2.20 (m, 4 H) 2.38 (br. s., 4H) 2.84 (br. s., 4 H) 3.86 (s, 5 H) 6.76 (s, 1 H) 7.64 (s, 5 H) 7.79 (s,1 H).

4-1034-(4-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamo+C1-yl)-ethyl]-benzenesulfonyl}-piperazin-1-yl)-4-oxo-butyricacid: MS M+1 630, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.09 (td, J=8.46, 3.54Hz, 2 H) 1.36-1.46 (m, 2 H) 1.50-1.61 (m, 3 H) 1.63-1.72 (m, 3 H) 2.11(t, J=7.20 Hz, 3 H) 2.37 (t, J=7.07 Hz, 2 H) 2.91 (s, 4 H) 3.49 (s, 6H)3.68-3.79 (m, 3 H) 3.84 (s, 4 H) 6.64 (d, J=8.59 Hz, 1 H) 7.59-7.66 (m,5 H)

4-1043-Cyclopentyl-2-[4-((S)-3-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 599, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.20 (m, 5 H) 1.23 (br.s., 1 H) 1.40-1.50 (m, 2 H) 1.52-1.63 (m, 3 H) 1.76 (br. s., 3 H)2.13-2.18 (m, 1 H) 2.20 (s, 1 H) 2.32-2.42 (m, 1 H) 3.10 (br. s., 1 H)3.30-3.40 (m, 2 H) 3.44-3.51 (m, 4 H) 3.65 (br. s., 12H) 3.70 (d, J=4.80Hz, 4 H) 3.72 (br. s., 1 H) 4.13 (t, J=7.45 Hz, 1 H) 6.98 (d, J=9.09 Hz,1 H) 7.69-7.74 (m, 2 H) 7.76-7.81 (m, 2 H) 7.88 (d, J=9.09 Hz, 1 H)12.57 (s, 1 H).

4-1053-Cyclopentyl-2-[4-((S)-3-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 591, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.14 (d, J=3.28 Hz, 1 H)1.15-1.24 (m, 4 H) 1.46 (dd, J=7.20, 4.67 Hz, 2 H) 1.58 (t, J=7.33 Hz, 2H) 1.63 (d, J=7.07 Hz, 1 H) 1.71 (br. s., 1 H) 1.74 (d, J=4.55 Hz, 1 H)1.83 (dd, J=13.52, 1.64 Hz, 1 H) 2.15-2.25 (m, 1 H) 2.44 (br. s., 1 H)3.09 (br. s., 1 H) 3.33 (br. s., 1H) 3.39 (br. s., 1 H) 3.60-3.71 (m, 3H) 4.25 (t, J=7.58 Hz, 1 H) 7.71-7.77 (m, 2 H) 7.77-7.83 (m, 2 H) 8.33(d, J=8.59 Hz, 1 H) 8.39-8.45 (m, 1 H) 8.52 (d, J=5.81 Hz, 2 H) 8.90 (d,J=6.57 Hz, 2 H) 13.20 (s, 1 H).

4-1063-Cyclopentyl-N-[5-(2-methoxy-ethylamino)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 573, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.09-1.20 (m, 2 H) 1.39-1.49(m, 2 H) 1.59 (qd, J=7.62, 7.45 Hz, 3 H) 1.68-1.79 (m, 3 H) 2.11-2.21(m, 1 H) 3.08 (d, J=4.80 Hz, 4 H) 3.22 (s, 4 H) 3.27 (s, 3 H) 3.41-3.49(m, 4 H) 4.09 (t, J=7.45 Hz, 1 H) 6.63 (d, J=8.84 Hz, 1 H) 7.67-7.74 (m,3 H) 7.76-7.81 (m, 2 H) 8.52 (s, 2 H) 12.41 (s, 1 H).

4-1073-Cyclopentyl-2-[4-(piperazine-1-sulfonyl)-phenyl]-N-(5-vinyl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 526, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.06 (s, 2H) 1.35 (dd,J=7.07, 4.80 Hz, 2 H) 1.43-1.54 (m, 3 H) 1.65 (d, J=8.34 Hz, 2 H)1.68-1.76 (m, 1 H) 2.07 (s, 1 H) 2.99 (d, J=4.80 Hz, 4 H) 3.09 (s, 4 H)4.06 (t, J=7.58 Hz, 1 H) 5.40 (dd, J=10.99, 1.39 Hz, 1 H) 6.14 (dd,J=17.43, 1.26 Hz, 1 H) 6.80 (dd, J=17.43, 10.86 Hz, 1H) 7.54 (d, J=8.34Hz, 1 H) 7.61-7.67 (m, 2 H) 7.67-7.72 (m, 2 H) 7.97 (d, J=8.34 Hz, 1 H)8.42 (s, 2 H) 12.79 (s, 1 H).

4-1083-Cyclopentyl-2-[4-(piperazine-1-sulfonyl)-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 577, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (br. s., 2 H) 1.46 (br.s., 2 H) 1.58 (d, J=5.81 Hz, 3 H) 1.74 (br. s., 2 H) 1.84 (br. s., 1 H)2.20 (br. s., 1 H) 3.13 (br. s., 7 H) 4.23 (br. s., 1 H) 7.73-7.84 (m, 4H) 8.27-8.36 (m, 1 H) 8.41 (d, J=8.59 Hz, 1 H) 8.48 (br. s., 2 H) 8.88(d, J=5.05 Hz, 4 H) 13.16 (br. s., 1 H).

4-1093-Cyclopentyl-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 585, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.09-1.20 (m, 2 H) 1.45 (dd,J=7.07, 4.55 Hz, 2 H) 1.52-1.63 (m, 3 H) 1.77 (dd, J=13.52, 6.69 Hz, 3H) 2.11-2.21 (m, 1 H) 3.12 (s, 4 H) 3.16 (s, 4 H) 3.42-3.50 (m, 4 H)3.65-3.74 (m, 4H) 4.14 (t, J=7.58 Hz, 1 H) 6.98 (d, J=9.09 Hz, 1 H)7.69-7.75 (m, 2 H) 7.76-7.81 (m, 2 H) 7.89 (d, J=9.09 Hz, 1 H) 8.91 (s,2 H) 12.59 (s, 1 H).

4-1103-Cyclopentyl-2-[4-(piperazine-1-sulfonyl)-phenyl]-N-(5-piperazin-1-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 585, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.20 (m, 1 H) 1.14 (dd,J=14.78, 3.92 Hz, 1 H) 1.45 (dd, J=7.33, 4.80 Hz, 2 H) 1.52-1.63 (m, 1H) 1.58 (d, J=7.83 Hz, 2 H) 1.76 (ddd, J=19.26, 7.01, 6.82 Hz, 3 H) 2.16(d, J=7.07 Hz, 1 H) 3.14 (d, J=11.37 Hz, 11H) 3.78 (br. s., 1 H) 3.76(d, J=5.31 Hz, 3 H) 4.17 (t, J=7.58 Hz, 1 H) 7.06 (d, J=9.09 Hz, 1 H)7.70-7.75 (m, 2 H) 7.75-7.81 (m, 2 H) 7.94 (d, J=9.09 Hz, 1 H) 9.05 (br.s., 1 H) 9.25 (br. s., 2 H) 12.66 (s, 1 H).

4-1113-Cyclopentyl-N-[5-(4-methyl-piperazin-1-yl)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(piperazine-1-sulfonyl)-phenyl]-propionamide:MS M+1 599, 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09-1.21 (m, 2 H) 1.45 (dd,J=7.20, 4.67 Hz, 2 H) 1.52-1.63 (m, 3 H) 1.76 (td, J=13.89, 6.82 Hz, 2H) 1.75 (d, J=6.57 Hz, 1 H) 2.15 (t, J=7.71 Hz, 1 H) 2.80 (d, J=4.55 Hz,3 H) 3.13 (br. s., 9 H) 3.28 (br. s., 2 H) 3.47 (br. s., 2 H) 4.37 (br.s., 2 H) 7.09 (d, J=9.09 Hz, 1 H) 7.69-7.75 (m, 2 H) 7.75-7.81 (m, 2 H)7.95 (d, J=8.84 Hz, 1 H) 9.01 (br. s., 2 H) 10.85 (br. s., 1 H) 12.66(s, 1 H).

4-1123-Cyclopentyl-2-[4-(piperazine-1-sulfonyl)-phenyl]-N-(5-pyridin-3-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 577, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.10-1.22 (m, 2 H) 1.45 (dd,J=7.33, 4.80 Hz, 2 H) 1.60 (td, J=15.22, 7.20 Hz, 3 H) 1.68-1.79 (m, 2H) 1.79-1.86 (m, 1 H) 2.20 (ddd, J=13.20, 7.96, 7.64 Hz, 1 H) 2.67-2.74(m, 4 H) 2.77 (d, J=4.80 Hz, 4 H) 4.14 (t, J=7.58 Hz, 1 H) 7.53 (dd,J=8.08, 4.80 Hz, 1 H) 7.71 (q, J=8.76 Hz, 4 H) 8.13-8.22 (m, 2 H) 8.48(dt, J=8.08, 2.02 Hz, 1 H) 8.63 (dd, J=4.67, 1.64 Hz, 1 H) 9.30 (d,J=2.27 Hz, 1 H).

4-1133-Cyclopentyl-2-[4-(4,7-diaza-spiro[2.5]octane-7-sulfonyl)-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS M+1 603, 1H NMR (400 MHz, DMSO-d6) δ ppm 0.43 (d, J=7.33 Hz, 3 H)1.16 (br. s., 2 H) 1.24 (s, 1 H) 1.45 (dd, J=7.33, 4.55 Hz, 2 H)1.53-1.65 (m, 3 H) 1.73 (br. s., 2 H) 1.82 (ddd, J=13.58, 7.07, 6.88 Hz,1 H) 2.18 (t, J=7.58 Hz, 1 H) 2.63-2.71 (m, 2 H) 2.72-2.83 (m, 4 H)4.08-4.16 (m, 1 H) 7.65-7.74 (m, 3 H) 7.70 (d, J=5.31 Hz, 3 H) 8.10 (d,J=6.32 Hz, 1 H) 8.10 (d, J=2.78 Hz, 1 H) 8.22 (s, 2 H) 8.70 (d, J=6.06Hz, 1 H) 8.70 (d, J=3.03 Hz, 1 H).

4-1143-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-trifluoromethyl-thiazolo[5,4-b]pyridin-2-yl)-propionamide:MS MH⁺=582, 1H NMR (400 MHz, DMSO-D6) δ ppm 1.15-1.30 (m, 2 H) 1.45-1.55(m, 2 H) 1.58-1.68 (m, 3 H) 1.73-1.83 (m, 2 H) 1.88-1.94 (m, 1H)2.19-2.30 (m, 1 H) 2.60-2.70 (m, 2H) 2.79 (s, 3 H) 3.12-3.33 (m, 2 H)3.46 (s, 2 H) 3.81-3.87 (m, 2 H) 4.28 (t, J=7.8 Hz, 1H) 7.80 (d, J=8.3Hz, 2 H) 7.86 (d, J=8.3 Hz, 2 H) 8.04 (d, J=8.4 Hz, 1H) 8.40 (d, J=8.4Hz, 1H) 10.26 (broad s, 1H)

4-1153-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-[5-(tetrahydro-pyran-4-ylamino)-thiazolo[5,4-b]pyridin-2-yl]-propionamideMS MH⁺=613, 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.15 (br. s., 2 H) 1.37-1.48(m, 4 H) 1.57 (br. s., 3 H) 1.78 (d, J=17.18 Hz, 1 H) 1.77 (d, J=6.06Hz, 2 H) 1.88 (br. s., 2 H) 2.16 (d, J=12.88 Hz, 1 H) 2.76 (s, 3 H) 3.15(br. s., 2 H) 3.43 (t, J=11.24 Hz, 5 H) 3.40 (br. s., 1 H) 3.88 (br. s.,4 H) 4.03-4.12 (m, 1 H) 6.58 (d, J=8.84 Hz, 1 H) 7.72 (d, J=7.58 Hz, 2H) 7.68 (s, 1 H) 7.76-7.81 (m, 2 H) 12.40 (s, 1 H)

4-1163-Cyclopentyl-N-[5-(4-dimethylamino-phenyl)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamideMS MH⁺=633, 1H NMR (400 MHz, DMSO-d₆) δ ppm 1.16 (br. s., 2 H) 1.45 (dd,J=7.45, 4.93 Hz, 2 H) 1.60 (d, J=8.08 Hz, 3 H) 1.75 (br. s., 1 H) 1.73(d, J=3.79 Hz, 1 H) 1.84 (d, J=7.07 Hz, 1 H) 2.18 (t, J=7.58 Hz, 1 H)2.76 (s, 3 H) 2.98 (s, 6 H) 3.15 (br. s., 2 H) 3.45 (br. s., 4 H) 3.80(br. s., 2 H) 4.16 (t, J=7.58 Hz, 1 H) 6.80 (d, J=9.09 Hz, 2 H)7.72-7.82 (m, 4 H) 7.97 (d, J=8.84 Hz, 2 H) 7.92 (d, J=8.59 Hz, 1 H)8.06 (d, J=8.59 Hz, 1 H) 12.80 (s, 1 H)

4-1174-(2-{3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazolo[5,4-b]pyridin-5-yl)-benzoic acid MS MH⁺=634, 1H NMR(400 MHz, DMSO-d₆) δ ppm 1.14 (d, J=6.32 Hz, 2 H) 1.37-1.48 (m, 1 H)1.43 (dd, J=7.33, 4.55 Hz, 2H) 1.62 (d, J=7.33 Hz, 1 H) 1.56 (d, J=2.53Hz, 2 H) 1.68-1.79 (m, 3 H) 2.10 (s, 3 H) 2.16 (dd, J=7.33, 5.81 Hz, 1H) 2.32 (t, J=4.17 Hz, 4 H) 2.87 (br. s., 4 H) 3.91 (br. s., 1 H) 7.67(s, 4 H) 7.94 (d, J=8.34 Hz, 3 H) 7.90 (s, 1 H) 8.01-8.07 (m, 2 H)

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon-patent publications referred to in this specification and/or listedin the Application Data Sheet are incorporated herein by reference, intheir entirety.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention.

Accordingly, the invention is not limited except as by the appendedclaims.

1. A compound of the formula

wherein Q combined together with the carbon and nitrogen atoms to whichit is attached form a 5- to 6-membered monocyclic heteroaromatic ringwhich is selected from the group consisting of

Q combined together with the carbon and nitrogen atoms to which it isattached form a 9- to 10-membered bicyclic heterocycle which is selectedfrom the group consisting of

R₁ and R₂ are, independently from each other, hydrogen, halogen, cyano,nitro, substituted alkoxy or optionally substituted alkyl, alkylthio,alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl,optionally substituted amino, aryl or heterocyclyl; or R₂ is absent; R₃is C₃-C₆ cycloalkyl; R₄ is hydrogen, halogen, cyano, lower alkyl orlower alkoxy; R₅ is hydrogen, optionally substituted alkyl, orcycloalkyl; R₆ is —(CR₇R₈)_(m)—W—R₉ in which R₇ and R₈ are,independently from each other, hydrogen, optionally substituted alkyl orcycloalkyl; or R₇ and R₈ combined are alkylene which together with thecarbon atom to which they are attached form a 3- to 7-membered ring; mis zero or an integer from 1 to 5; W is —NR₁₀— in which R₁₀ is hydrogen,optionally substituted alkyl or heterocyclyl; or R₁₀ is —C(O)R₁₁,—C(O)OR₁₁, or —C(O)NR₁₂R₁₃ in which R₁₁ and R₁₂ are, independently fromeach other, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl,aralkyl or heteroaralkyl; R₁₃ is hydrogen or lower alkyl; or R₁₃ and R₁₂combined are alkylene which together with the nitrogen atom to whichthey are attached form a 4- to 7-membered ring; or W is absent; R₉ ishydrogen, optionally substituted C₁-C₇ alkyl, cycloalkyl, aryl orheterocyclyl; or R₉ and R₁₀ combined are alkylene which together withthe nitrogen atom to which they are attached form a 4- to 7-memberedring; or R₆ and R₅ combined are alkylene which together with thenitrogen atom to which they are attached form a 4- to 7-membered ringwhich may be optionally substituted, or may contain 1 to 3 otherheteroatoms selected from oxygen, nitrogen and sulfur, or may be part ofanother ring; or a pharmaceutically acceptable salt thereof.
 2. Thecompound according to claim 1, wherein R₁ is hydrogen, halogen, cyano,nitro, substituted alkoxy or optionally substituted alkyl, alkylthio,alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl,optionally substituted amino, aryl or heterocyclyl; or R₂ is absent R₃is cyclopentyl; R₄ is hydrogen; R₅ is hydrogen or lower alkyl; R₆ is—(CR₇R₈)_(m—W—R) ₉ in which R₇ and R₈ are independently hydrogen oroptionally substituted lower alkyl; m is zero or an integer from 1 to 5;W is —NR₁₀— in which R₁₀ is hydrogen or lower alkyl; or R₁₀ is —C(O)R₁₁,—C(O)OR₁₁, or —C(O)NR₁₂R₁₃ in which R₁₁ and R₁₂ are, independently fromeach other, optionally substituted alkyl, cycloalkyl, aryl, heteroaryl,aralkyl or heteroaralkyl; R₁₃ is hydrogen or lower alkyl; or R₁₃ and R₁₂combined are alkylene which together with the nitrogen atom to whichthey are attached form a 5- to 7-membered ring; or W is absent; R₉ ishydrogen, optionally substituted C₁-C₇ alkyl, cycloalkyl, aryl orheterocyclyl; or R₉ and R₁₀ combined are alkylene which together withthe nitrogen atom to which they are attached form a 5- to 7-memberedring; or R₆ and R₅ combined are alkylene which together with thenitrogen atom to which they are attached form a 4- to 7-membered ringwhich may be optionally substituted, or may contain 1 to 3 otherheteroatoms selected from oxygen, nitrogen and sulfur, or may be part ofanother ring; or a pharmaceutically acceptable salt thereof.
 3. Thecompound according to claim 2, wherein Q combined together with thecarbon and nitrogen atoms to which it is attached form a 5- to6-membered monocyclic heteroaromatic ring which is selected from thegroup consisting of

R₅ is hydrogen or lower alkyl; R₆ is —(CR₇R₈)_(m)—W—R₉ in which R₇ andR₈ are hydrogen; m is an integer from 2 to 5; W is —NR₁₀— in which R₁₀is hydrogen or lower alkyl; or R₁₀ is —C(O)R₁₁, —C(O)OR₁₁, or—C(O)NR₁₂R₁₃ in which R₁₁ and R₁₂ are, independents from each other,optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl orheteroaralkyl; R₁₃ is hydrogen or lower alkyl; or R₁₃ and R₁₂ combinedare alkylene which together with the nitrogen atom to which they areattached form a 5- to 7-membered ring; or W is absent; R₉ is hydrogen,optional substituted C₁-C₇ alkyl, cycloalkyl, aryl or heterocyclyl; orR₉ and R₁₀ combined are alkylene which together with the nitrogen atomto which they are attached form a 5- to 7-membered ring; or apharmaceutically acceptable salt thereof.
 4. The compound according toclaim 3 of the formula

wherein R₁ is hydrogen, halogen, cyano, trifluoromethyl, alkylthio orcarboxy; R₂ is absent; R₅ is hydrogen or lower alkyl; R₉ is hydrogen,optionally substituted C₁-C₇ alkyl, cycloalkyl, aryl or heterocyclyl;R₁₀ is hydrogen or lower alkyl; or R₁₀ is —C(O)R₁₁, —C(O)OR₁₁, or—C(O)NR₁₂R₁₃ in which R₁₁ and R₁₂ are, independently from each other,optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl orheteroaralkyl; R₁₃ is hydrogen or lower alkyl; or R₁₃ and R₁₂ combinedare alkylene which together with the nitrogen atom to which they areattached form a 5- to 7-membered ring; or R₁₀ and R₉ combined arealkylene which together with the nitrogen atom to which they areattached form a 5- to 7-membered ring; or a pharmaceutically acceptablesalt thereof.
 5. The compound according to claim 4, wherein Q combinedtogether with the carbon and nitrogen atoms to which it is attached forma 5- to 6-membered monocyclic heteroaromatic ring which is selected fromthe group consisting of

or a pharmaceutically acceptable salt thereof.
 6. The compound accordingto claim 2, wherein Q combined together with the carbon and nitrogenatoms to which it is attached form a 5- to 6-membered monocyclicheteroaromatic ring which is selected from the group consisting of

R₆ and R₅ combined are alkylene which together with the nitrogen atom towhich they are attached form a 4- to 7-membered ring which may beoptionally substituted, or may contain 1 to 3 other heteroatoms selectedfrom oxygen, nitrogen and sulfur, or may be part of another ring; or apharmaceutically acceptable salt thereof.
 7. The compound according toclaim 6 of the formula

wherein R₁ is hydrogen, halogen, cyano, trifluoromethyl, alkylthio orcarboxy; R₂ is absent; R₁₄ is hydrogen, optionally substituted loweralkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R₁₄ is—C(O)R₁₉, —C(O)OR₁₉, or —C(O)NR₂₀R₂₁ in which R₁₉ and R₂₀ are,independently from each other, optionally substituted alkyl, cycloalkyl,aryl, heteroaryl, aralkyl or heteroaralkyl; R₂₁ is hydrogen or loweralkyl; or R₂₁ and R₂₀ combined are alkylene which together with thenitrogen atom to which they are attached form a 5- to 7-membered ring;R₁₅, R₁₆, R₁₇ and R₁₈ are, independently from each other, hydrogen,halogen, hydroxy, alkoxy, free or esterified carboxy, optionallysubstituted lower alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl orheterocyclyl; or a pharmaceutically acceptable salt thereof.
 8. Thecompound according to claim 7, wherein Q combined together with thecarbon and nitrogen atoms to which it is attached form a 5- to6-membered monocyclic heteroaromatic ring which is selected from thegroup consisting of

or a pharmaceutically acceptable salt thereof.
 9. The compound accordingto claim 8, wherein R₁₄ is methyl; or a pharmaceutically acceptable saltthereof.
 10. The compound according to claim 8, wherein R₁₄, R₁₅, R₁₆,R₁₇ and R₁₈ are, independently from each other, hydrogen or methyl; or apharmaceutically acceptable salt thereof.
 11. The compound according toclaim 6 of the formula

wherein R₁ is hydrogen, halogen, cyano, trifluoromethyl, alkylthio orcarboxy; R₂ is absent; R₂₂ is hydrogen, optionally substituted loweralkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R₂₂ is—C(O)R₁₉, —C(O)OR₁₉, or —C(O)NR₂₀R₂₁ in which R₁₉ and R₂₀ are,independently from each other, optionally substituted alkyl, cycloalkyl,aryl, heteroaryl, aralkyl or heteroaralkyl; R₂₁ is hydrogen or loweralkyl; or R₂₁ and R₂₀ combined are alkylene which together with thenitrogen atom to which they are attached form a 5- to 7-membered ring;R₂₃, R₂₄, R₂₅ and R₂₆ are, independently from each other, hydrogen,halogen, hydroxy, alkoxy, free or esterified carboxy, optionallysubstituted lower alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl orheterocyclyl; or R₂₂ and R₂₅ combined are alkylene which together withthe nitrogen and carbon atoms to which they are attached form a 4- to7-membered ring; or R₂₅ and R₂₆ combined are alkylene which togetherwith the carbon atom to which they are attached form a 3- to 7-memberedring; or a pharmaceutically acceptable salt thereof.
 12. The compoundaccording to claim 11, wherein Q combined together with the carbon andnitrogen atoms to which it is attached form a 5- to 6-memberedmonocyclic heteroaromatic ring which is selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.
 13. The compoundaccording to claim 2, wherein Q combined together with the carbon andnitrogen atoms to which it is attached form a 9- to 10-membered bicyclicheterocycle which is selected from the group consisting of

R₅ is hydrogen or lower alkyl; R₆ is —(CR₇R₈)_(m)—W—R₉ in which R₇ andR₈ are hydrogen; m is an integer from 2 to 5; W is —NR₁₀— in which R₁₀is hydrogen or lower alkyl; or R₁₀ is —C(O)R₁₁, —C(O)OR₁₁, or—C(O)NR₁₂R₁₃ in which R₁₁ and R₁₂ are, independently from each other,optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl orheteroaralkyl; R₁₃ is hydrogen or lower alkyl; or R₁₃ and R₁₂ combinedare alkylene which together with the nitrogen atom to which they areattached form a 5- to 7-membered ring; or W is absent; R₉ is hydrogen,optionally substituted C₁-C₇ alkyl, cycloalkyl, aryl or heterocyclyl; orR₉ and R₁₀ combined are alkylene which together with the nitrogen atomto which they are attached form a 5- to 7-membered ring; or apharmaceutically acceptable salt thereof.
 14. The compound according toclaim 13 of the formula

wherein R₁ is hydrogen, halogen, cyano, trifluoromethyl, alkylthio orcarboxy; R₂ is absent; R₅ is hydrogen or lower alkyl; R₉ is hydrogen,optionally substituted C₁-C₇ alkyl, cycloalkyl, aryl or heterocyclyl;R₁₀ is hydrogen or lower alkyl; or R₁₀ is —C(O)R₁₁, —C(O)OR₁₁, or—C(O)NR₁₂R₁₃ in which R₁₁ and R₁₂ are, independently from each other,optionally substituted alkyl, cycloalkyl, aryl, heteroaryl, aralkyl orheteroaralkyl; R₁₃ is hydrogen or lower alkyl; or R₁₃ and R₁₂ combinedare alkylene which together with the nitrogen atom to which they areattached form a 5- to 7-membered ring; or R₁₀ and R₉ combined arealkylene which together with the nitrogen atom to which they areattached form a 5- to 7-membered ring; or a pharmaceutically acceptablesalt thereof.
 15. The compound according to claim 14, wherein Q combinedtogether with the carbon and nitrogen atoms to which it is attached forma 9- to 10-membered bicyclic heterocycle which is selected from thegroup consisting of

or a pharmaceutically acceptable salt thereof.
 16. The compoundaccording to claim 2, wherein Q combined together with the carbon andnitrogen atoms to which it is attached form a 9- to 10-membered bicyclicheterocycle which is selected from the group consisting of

R₆ and R₅ combined are alkylene which together with the nitrogen atom towhich they are attached form a 4- to 7-membered ring which may beoptionally substituted, or may contain 1 to 3 other heteroatoms selectedfrom oxygen, nitrogen and sulfur, or may be part of another ring; or apharmaceutically acceptable salt thereof.
 17. The compound according toclaim 16 of the formula

wherein R₁ is hydrogen, halogen, cyano, trifluoromethyl, alkylthio orcarboxy; R₂ is absent; R₁₄ is hydrogen, optionally substituted loweralkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R₁₄ is—C(O)R₁₉, —C(O)OR₁₉, or —C(O)NR₂₀R₂₁ in which R₁₉ and R₂₀ are,independently from each other, optionally substituted alkyl, cycloalkyl,aryl, heteroaryl, aralkyl or heteroaralkyl; R₂₁ is hydrogen or loweralkyl; or R₂₁ and R₂₀ combined are alkylene which together with thenitrogen atom to which they are attached form a 5- to 7-membered ring;R₁₅, R₁₆, R₁₇ and R₁₈ are, independently from each other, hydrogen,halogen, hydroxy, alkoxy, free or esterified carboxy, optionallysubstituted lower alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl orheterocyclyl; or a pharmaceutically acceptable salt thereof.
 18. Thecompound according to claim 17, wherein Q combined together with thecarbon and nitrogen atoms to which it is attached form a 9- to10-membered bicyclic heterocycle which is selected from the groupconsisting of

or a pharmaceutically acceptable salt thereof.
 19. The compoundaccording to claim 18, wherein R₁₄ is methyl; or a pharmaceuticallyacceptable salt thereof.
 20. The compound according to claim 18, whereinR₁₄, R₁₅, R₁₆, R₁₇ and R₁₈ are, independently from each other, hydrogenor methyl; or a pharmaceutically acceptable salt thereof.
 21. Thecompound according to claim 16 of the formula

wherein R₁ is hydrogen, halogen, cyano, trifluoromethyl, alkylthio orcarboxy; R₂ is absent; R₂₂ is hydrogen, optionally substituted loweralkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroaralkyl; or R₂₂ is—C(O)R₁₉, —C(O)OR₁₉, or —C(O)NR₂₀R₂₁ in which R₁₉ and R₂₀ are,independently from each other, optionally substituted alkyl, cycloalkyl,aryl, heteroaryl, aralkyl or heteroaralkyl; R₂₁ is hydrogen or loweralkyl; or R₂₁ and R₂₀ combined are alkylene which together with thenitrogen atom to which they are attached form a 5- to 7-membered ring;R₂₃, R₂₄, R₂₅ and R₂₆ are, independently from each other, hydrogen,halogen, hydroxy, alkoxy, free or esterified carboxy, optionallysubstituted lower alkyl, cycloalkyl, aryl, aralkyl, heteroaralkyl orheterocyclyl; or R₂₂ and R₂₅ combined are alkylene which together withthe nitrogen and carbon atoms to which they are attached form a 4- to7-membered ring; or R₂₅ and R₂₆ combined are alkylene which togetherwith the carbon atom to which they are attached form a 3- to 7-memberedring; or a pharmaceutically acceptable salt thereof.
 22. The compoundaccording to claim 21, wherein Q combined together with the carbon andnitrogen atoms to which it is attached form a 9- to 10-membered bicyclicheterocycle which is selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 23. The method for theactivation of glucokinase activity in mammals which method comprisesadministering to a mammal, in need thereof, a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof.
 24. A method for the treatment of conditions associated withglucokinase activity in mammals, comprising: administering to a mammal,in need thereof, a therapeutically effective amount of a compound ofclaim 1, or a pharmaceutically acceptable salt thereof.
 25. The methodaccording to claim 24, which method comprises administering atherapeutically effective amount of said compound in combination with atherapeutically effective amount of an anti-diabetic agent, ahypolipidemic agent, an anti-obesity agent or an anti-hypertensiveagent.
 26. A method for the treatment of impaired glucose tolerance,type 2 diabetes and obesity, comprising: administering to a mammal inneed thereof a therapeutically effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof.
 27. A pharmaceuticalcomposition, comprising: a therapeutically effective amount of acompound of claim 1, or a pharmaceutically acceptable salt thereof, incombination with one or more pharmaceutically acceptable carriers.
 28. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 1, or a pharmaceutically acceptable salt thereof,in combination with a therapeutically effective amount of ananti-diabetic agents, a hypolipidemic agent, an anti-obesity agent or ananti-hypertensive agent.
 29. A compound of the formula

wherein Q combined together with the carbon and nitrogen atoms to whichit is attached form a 5- to 6-membered monocyclic heteroaromatic ringwhich is selected from the group consisting of

Q combined together with the carbon and nitrogen atoms to which it isattached form a 9- to 10-membered bicyclic heterocyde which is selectedfrom the group consisting of

R₁ and R₂ are, independently from each other, hydrogen, halogen, cyano,nitro, substituted alkoxy or optionally substituted alkyl, optionallysubstituted alkenyl, alkynyl, alkylthio, alkylthiono, sulfonyl, free oresterified carboxy, carbamoyl, sulfamoyl, optionally substituted amino,aryl, aryloxy or heterocyclyl; R₃ is C₃-C₆ cycloalkyl; R₄ is hydrogen,halogen, cyano, lower alkyl or lower alkoxy; R₅ is hydrogen, optionallysubstituted alkyl, or cycloalkyl; R₆ is —(CR₇R₈)_(m)—W—R₉ in which R₇and R₈ are, independently from each other, hydrogen, optionallysubstituted alkyl or cycloalkyl; or R₇ and R₈ combined are alkylenewhich together with the carbon atom to which they are attached form a 3-to 7-membered ring; m is zero or an integer from 1 to 5; W is —NR₁₀— inwhich R₁₀ is hydrogen, optionally substituted alkyl or heterocyclyl; orR₁₀ is —C(O)R₁₁, —C(O)OR₁₁, or —C(O)NR₁₂R₁₃ in which R₁₁ and R₁₂ are,independently from each other, optionally substituted alkyl, cycloalkyl,aryl, heteroaryl, aralkyl or heteroaralkyl; R₁₃ is hydrogen or loweralkyl; or R₁₃ and R₁₂ combined are alkylene which together with thenitrogen atom to which they are attached form a 4- to 7-membered ring;or W is absent; R₉ is hydrogen, optionally substituted C₁-C₇ alkyl,cycloalkyl, aryl or heterocyclyl; or R₉ and R₁₀ combined are alkylenewhich together with the nitrogen atom to which they are attached form a4- to 7-membered ring; or R₆ and R₅ combined are alkylene which togetherwith the nitrogen atom to which they are attached form a 4- to7-membered ring which may be optionally substituted, or may contain 1 to3 other heteroatoms selected from oxygen, nitrogen and sulfur, or may bepart of another ring; or a pharmaceutically acceptable salt thereof. 30.A compound selected from the group consisting of:(R)-3-Cyclopentyl-N-isoquinolin-1-yl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-N-(1-methyl-1H-benzoimidazol-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-[1,3,4]thiadiazol-2-yl-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-quinolin-2-yl-propionamide;(R)—N-(6-Chloro-pyridazin-3-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-methyl-thiazol-2-yl)-propionamide;2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazole-4-carboxylicacid;2-[(R)-3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-propionylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylicacid tert-butyl ester;(R)-3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-(5-methyl-4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-pyrazin-2-yl-propionamide;(R)-3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-pyridin-2-yl-propionamide;(R)-3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-(6-trifluoromethyl-pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-pyrimidin-2-yl-propionamide;(R)-3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-N-thiazol-2-yl-propionamide;6-[(R)-3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-propionylamino]-nicotinicacid;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(1H-tetrazol-5-yl)-propionamide;(R)—N-(5-Chloro-thiazol-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(4-methyl-thiazol-2-yl)-propionamide;(R)-3-Cyclopentyl-N-(1H-indazol-3-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-propionamide;(R)—N-(5-Bromo-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;6-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}nicotinicacid;2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazol-4-yl)-aceticacid ethyl ester;(R)—N-Benzothiazol-2-yl-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)—N-(6-Bromo-benzothiazol-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-N-(6-methanesulfonyl-benzothiazol-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-phenoxy-thiazolo[5,4-b]pyridin-2-yl)-propionamide;2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazol-4-yl)-aceticacid;2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-benzothiazole-6-carboxylicacid ethyl ester;2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]propionylamino}-benzothiazole-6-carboxylicacid;2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-benzothiazole-6-carboxylicacid;2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-3-trifluoromethyl-phenyl]-propionylamino}benzothiazole-6-carboxylicacid;2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-benzothiazole-6-carboxylicacid (2-methoxy-ethyl)-amide;3-[(2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-benzothiazole-6-carbonyl)-amino]-propionicacid;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(6-trifluoromethoxy-benzothiazol-2-yl)-propionamide;(R)—N-(5-Chloro-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]propionylamino}-thiazolo[5,4-b]pyridin-5-yloxy)-aceticacid;(R)-3-Cyclopentyl-N-(5-fluoro-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-vinyl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-N-(5-ethyl-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-pyridin-3-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-phenyl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-3-trifluoromethyl-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-N-[5-(2-methoxy-ethoxy)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;4-(2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazolo[5,4-b]pyridin-5-yloxy)-butyricacid;(R)-3-Cyclopentyl-N-{5-[(2-methoxy-ethyl)-methyl-amino]-thiazolo[5,4-b]pyridin-2-yl}-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;3-(2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazolo[5,4-b]pyridin-5-yloxy)-2,2-dimethyl-propionicacid;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-[5-(4-methyl-piperazin-1-yl)-thiazolo[5,4-b]pyridin-2-yl]-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-piperidin-1-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazolo[5,4-b]pyridine-5-carboxylicacid (2-methoxy-ethyl)-methyl-amide(R)-3-Cyclopentyl-N-[5-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-[5-(2-methyl-pyridin-4-yl)-thiazolo[5,4-b]pyridin-2-yl]-propionamide;(R)-3-Cyclopentyl-N-(5-ethynyl-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-pyrimidin-5-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazolo[5,4-b]pyridine-5-carboxylicacid (2-methoxy-ethyl)-amide;2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazolo[5,4-b]pyridine-5-carboxylicacid dimethylamide;(R)-3-Cyclopentyl-N-[5-(2-hydroxy-ethoxy)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-pyridinyl-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-[5-(morpholine-4-carbonyl)-thiazolo[5,4-b]pyridin-2-yl]-propionamide;(R)-3-Cyclopentyl-N-(5-isopropoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)—N-(5-Benzyl-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)—N-(5-Amino-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-33-Cyclopentyl-N-[5-(2-methoxy-ethylamino)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-2-[3-Chloro-4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-chloro-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-propionamide;(R)—N-(5-Bromo-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-3-trifluoromethyl-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-3-trifluoromethyl-phenyl]-N-[5-(4-methyl-piperazin-1-yl)-thiazolo[5,4-b]pyridin-2-yl]-propionamide;(R)-2-[3-Chloro(4-methyl-piperazine-1-sulfonyl)-phenyl]-3-cyclopentyl-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-N-[5-(2-cyclopropyl-pyridin-4-yl)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)—N-(5-Chloro-thiazolo[5,4-b]pyridin-2-yl)-3-cyclohexyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-2-[3-Chloro-4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-3-cyclopentyl-N-[5-(4-methyl-piperazin-1-yl)-thiazolo[5,4-b]pyridin-2-yl]-propionamide;(R)-3-Cyclopentyl-2-[4-((S)-3,4-dimethyl-piperazine-1-sulfonyl)-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-[4-((S)-3,4-dimethyl-piperazine-1-sulfonyl)-phenyl]-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-4-{4-[2-Cyclopentyl-1-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-1-methyl-piperazine-2-carboxylicacid methyl ester;(R)-4-{4-[2-Cyclopentyl-1-(5-pyridinyl-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-1-methyl-piperazine-2-carboxylicacid;2-{(R)-3-Cyclopentyl-2-[4-(2-methoxy-ethylsulfamoyl)-phenyl]-propionylamino}-benzothiazole-6-carboxylicacid;2-((R)-3-Cyclopentyl-2-{4-[(2-methoxy-ethyl)-methyl-sulfamoyl]phenyl}-propionylamino)-benzothiazole-6-carboxylicacid;(R)—N-(5-Chloro-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(2-methoxy-ethylsulfamoyl)-phenyl]-propionamide;(R)—N-(5-Bromo-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-[4-(4-methyl-4,7-diaza-spiro[2.5]octane-7-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-4,7-diaza-spiro[2.5]octane-7-sulfonyl)-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-4,7-diaza-spiro[2.5]octane-7-sulfonyl)-phenyl]-N-[5-(4-methyl-piperazin-1-yl)-thiazolo[5,4-b]pyridin-2-yl]propionamide;(R)-3-Cyclopentyl-2-[4(4-methyl-4,7-diaza-spiro[2.5]octane-7-sulfonyl)-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(3,3,4-trimethyl-piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-2-(4-Butyrylsulfamoyl-phenyl)-3-cyclopentyl-N-(5-methoxy-thiazolo[5,4b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-N-(5-methoxy-thiazolo[5,4b]pyridin-2-yl)-2-{4-[4-(2-oxo-2-piperidin-1-yl-ethyl)-piperazine-1-sulfonyl]-phenyl}-propionamide;(R)-3-Cyclopentyl-2-{4-[4(isopropylcarbamoyl-methyl)-piperazine-1-sulfonyl]-phenyl}-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-propionamide;1-{4-[(R)-2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperidine-4-carboxylicacid;1-{4-[(R)-2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperidine-3-carboxylicacid;4-{4-[(R)-2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperazine-2-carboxylicacid;1-{4-[(R)-2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-4-methyl-piperazine-2-carboxylicacid;1-{4-[(R)-2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperazine-2-carboxylicacid;1-{4-[(R)-2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-pyrrolidine-3-carboxylicacid;4-{4-[(R)-2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-1-methyl-piperazine-2-carboxylicacid;{2-[(R)-3-Cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-propionylamino]-thiazolo[5,4-b]pyridin-5-yloxy}-aceticacid;(R)—N-(5-Carbamoylmethoxy-thiazolo[5,4-b]pyridin-2-yl)-3-cyclopentyl-2-(4-diethylsulfamoyl-phenyl)-propionamide;3-(4-{4-[(R)-2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4b]pyridin-2-ylcarbamoyl)-ethyl]benzenesulfonylamino}-piperidin-1-yl)-propionicacid;(R)-1-{4-[2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperidine-2-carboxylicacid;3-(4-{4-[(R)-2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperazin-1-yl)-propionicacid;4-(4-{4-[(R)-2-Cyclopentyl-1-(5-methoxy-thiazolo[5,4-b]pyridin-2-ylcarbamoyl)-ethyl]-benzenesulfonyl}-piperazin-1-yl)-4-oxo-butyricacid;(R)-3-Cyclopentyl-2-[4-((S)-3-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-[4-((S)-3-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-N-[5-(2-methoxy-ethylamino)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(piperazine-1-sulfonyl)-phenyl]-N-(5-vinyl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-[4-(piperazine-1-sulfonyl)-phenyl]-N-(5-pyridin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-N-(5-morpholin-4-yl-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4-(piperazine-1-sulfonyl)-phenyl]-N-(5-piperazin-1-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-N-[5-(4-methyl-piperazin-1-yl)-thiazolo[5,4b]pyridin-2-yl]-2-[4-(piperazine-1-sulfonyl)-phenyl]-propionamide;(R)-3-Cyclopentyl-2-[4(piperazine-1-sulfonyl)-phenyl]-N-(5-pyridin-3-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-[4-(4,7-diaza-spiro[2.5]octane-7-sulfonyl)-phenyl]-N-(5-pyridinyl-4-yl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-(5-trifluoromethyl-thiazolo[5,4-b]pyridin-2-yl)-propionamide;(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-N-[5-(tetrahydro-pyran-4-ylamino)-thiazolo[5,4-b]pyridin-2-yl]-propionamide;(R)-3-Cyclopentyl-N-[5-(4-dimethylamino-phenyl)-thiazolo[5,4-b]pyridin-2-yl]-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide;and4-(2-{(R)-3-Cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionylamino}-thiazolo[5,4-b]pyridin-5-yl)-benzoicacid, or a pharmaceutically acceptable salt thereof.
 31. A compound ofthe formula

wherein Q combined together with the carbon and nitrogen atoms to whichit is attached form a 5- to 6-membered monocyclic heteroaromatic ringwhich is selected from the group consisting of

Q combined together with the carbon and nitrogen atoms to which it isattached form a 9- to 10-membered bicyclic heterocycle which is selectedfrom the group consisting of

R₁ and R₂ are, independently from each other, hydrogen, halogen, cyano,nitro, substituted alkoxy or optionally substituted alkyl, alkylthio,alkylthiono, sulfonyl, free or esterified carboxy, carbamoyl, sulfamoyl,optionally substituted amino, aryl or heterocyclyl; or R₂ is absent; R₃is C₃-C₆ cycloalkyl; or C₃-C₆ heterocyclyl; R₄ is hydrogen, halogen,cyano, lower alkyl or lower alkoxy; R₆ and R₅ combined are alkylenewhich together with the nitrogen atom to which they are attached form a4- to 7-membered ring which may be optionally substituted, or maycontain 1 to 3 other heteroatoms selected from oxygen, nitrogen andsulfur, or may be part of another ring; or a pharmaceutically acceptablesalt thereof.